MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-kB ACTIVITY AND USE THEREOF

ABSTRACT

Novel non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, and/or AP-1, and/or NF-κB activity including inflammatory and immune diseases, obesity and diabetes having the structure of formula (I), its enantiomers, diastereomers, or a pharmaceutically-acceptable salt, or hydrate, thereof, wherein (Ia) is heterocycle or heteroaryl; J, Ja, E, F, G, Ma, M, Q, Za and Z are as defined herein. Also provided are pharmaceutical compositions and methods of treating inflammatory- or immune-associated diseases and obesity and diabetes employing said compounds.

FIELD OF THE INVENTION

The present invention relates to new non-steroidal compounds which areeffective modulators of the glucocorticoid receptor, and/or AP-1, and/orNF-κB activity and thus are useful in treating diseases such asinflammatory or immune associated diseases, and to a method for usingsuch compounds to treat these and related diseases.

BACKGROUND OF THE INVENTION

The transcription factors NF-κB and AP-1 are involved in regulating theexpression of a number of genes involved in mediating inflammatory andimmune responses. NF-κB regulates the transcription of genes includingTNF-α, IL-1, IL-2, IL-6, adhesion molecules (such as E-selectin) andchemokines (such as Rantes), among others. AP-1 regulates the productionof the cytokines TNF-α, IL-1, IL-2, as well as, matrix metalloproteases.Drug therapies targeting TNF-α, a gene whose expression is regulated byboth NF-κB and AP-1, have been shown to be highly efficacious in severalinflammatory human diseases including rheumatoid arthritis and Crohn'sdisease. Accordingly, NF-κB and AP-1 play key roles in the initiationand perpetuation of inflammatory and immunological disorders. SeeBaldwin, A. S., Journal of Clin. Investigation, 107:3 (2001); Firestein,G. S., and Manning, A. M., Arthritis and Rheumatism, 42:609 (1999); andPeltz, G., Curr. Opin. in Biotech., 8:467 (1997).

There are many signaling molecules (kinases and phosphatases) upstreamof AP-1 and NF-κB which are potential therapeutic drug targets. Thekinase JNK plays an essential role in regulating the phosphorylation andsubsequent activation of c-jun, one of the subunits which constitute theAP-1 complex (fos/c-jun). Compounds which inhibit JNK have been shown tobe efficacious in animal models of inflammatory disease. See Manning, A.M. and Davis, R. J., Nature Rev. Drug Disc., 2:554 (2003). A kinasecritical to the activation of NF-κB is the IκB kinase (IKK). This kinaseplays a key role in the phosphorylation of IκB. Once IκB isphosphorylated it undergoes degradation leading to the release of NF-κBwhich can translocate into the nucleus and activate the transcription ofthe genes described above. An inhibitor of IKK has been shown to beefficacious in animal models of inflammatory disease. See Burke, J. R.,Curr. Opin. Drug Discov. Devel., 6(5):720-728, (September 2003).

In addition to inhibiting signaling cascades involved in the activationof NF-κB and AP-1, the glucocorticoid receptor has been shown to inhibitthe activity of NF-κB and AP-1 via direct physical interactions. Theglucocorticoid receptor (GR) is a member of the nuclear hormone receptorfamily of transcription factors, and a member of the steroid hormonefamily of transcription factors. Affinity labeling of the glucocorticoidreceptor protein allowed the production of antibodies against thereceptor which facilitated cloning the glucocorticoid receptors. Forresults in humans see Weinberger et al., Science, 228:740-742 (1985);Weinberger et al., Nature, 318:670-672 (1986) and for results in ratssee Miesfeld, R., Nature, 312:779-781 (1985).

Glucocorticoids which interact with GR have been used for over 50 yearsto treat inflammatory diseases. It has been clearly shown thatglucocorticoids exert their anti-inflammatory activity via theinhibition by GR of the transcription factors NF-κB and AP-1. Thisinhibition is termed transrepression. It has been shown that the primarymechanism for inhibition of these transcription factors by GR is via adirect physical interaction. This interaction alters the transcriptionfactor complex and inhibits the ability of NF-κB and AP-1 to stimulatetranscription. See Jonat, C. et al., Cell, 62:1189 (1990); Yang-Yen, H.F. et al., Cell, 62:1205 (1990); Diamond, M. I. et al., Science,249:1266 (1990); and Caldenhoven, E. et al., Mol. Endocrinol., 9:401(1995). Other mechanisms such as sequestration of co-activators by GRhave also been proposed. See Kamei, Y. et al., Cell, 85:403 (1996); andChakravarti, D. et al., Nature, 383:99 (1996).

In addition to causing transrepression, the interaction of aglucocorticoid with GR can cause GR to induce transcription of certaingenes. This induction of transcription is termed transactivation.Transactivation requires dimerization of GR and binding to aglucocorticoid response element (GRE).

Recent studies using a transgenic GR dimerization defective mouse whichcannot bind DNA have shown that the transactivation (DNA binding)activities of GR could be separated from the transrepressive (non-DNAbinding) effect of GR. These studies also indicate that many of the sideeffects of glucocorticoid therapy are due to the ability of GR to inducetranscription of various genes involved in metabolism, whereas,transrepression, which does not require DNA binding leads to suppressionof inflammation. See Reichardt, H. M. et al., Cell, 93:531 (1998) andReichardt, H. M., EMBO J., 20:7168 (2001).

Compounds that modulate AP-1 and NF-κB activity would be useful in thetreatment of inflammatory and immune diseases and disorders such asosteoarthritis, rheumatoid arthritis, multiple sclerosis, asthma,inflammatory bowel disease, transplant rejection and graft vs. hostdisease.

Also, with respect to the glucocorticoid receptor pathway, it is knownthat glucocorticoids are potent anti-inflammatory agents. However theirsystemic use is limited by side effects. Compounds that retain theanti-inflammatory efficacy of glucocorticoids while minimizing the sideeffects such as diabetes, osteoporosis and glaucoma would be of greatbenefit to a very large number of patients with inflammatory diseases.

Additionally concerning GR, the art is in need of compounds thatantagonize transactivation. Such compounds may be useful in treatingmetabolic diseases associated with increased levels of glucocorticoid,such as diabetes, osteoporosis and glaucoma.

Additionally concerning GR, the art is in need of compounds that causetransactivation. Such compounds may be useful in treating metabolicdiseases associated with a deficiency in glucocorticoid. Such diseasesinclude Addison's disease.

DESCRIPTION OF THE INVENTION

The present invention relates to new non-steroidal compounds which areeffective modulators of the glucocorticoid receptor, and/or AP-1, and/orNF-κB activity and thus are useful in treating diseases such asinflammatory or immune associated diseases, and to a method for usingsuch compounds to treat these and related diseases.

In accordance with one aspect of the invention, compounds are providedhaving the structure of formula I

its enantiomers, diastereomers, tautomers, a prodrug ester thereof, or apharmaceutically-acceptable salt, or hydrate, thereof, wherein:

-   the side chain group

is attached to the bicyclic ring

at the 5- or 6- position;

is heterocyclo or heteroaryl;

-   E is selected from —N—, —NR₁—, —O—, C(═O)—, —S—, —SO₂—, and —CR₂—;-   F is selected from —N—, —NR_(1a)—, —O—, —C(═O)—, —S—, SO₂—, and    —CR_(2a)—;-   G is selected from N, —NR_(1b)—, —O—, —C(═O)—, —S—, SO₂—, and    —CR_(2b)—, provided that the E-F-G containing heterocyclic ring    formed does not contain a S—S or S—O bond, and at least one of E, F    and G is a heteroatom;-   J is C or N;-   J_(a) is C or N, provided that only one of J and J_(a) can be N, but    each of J and J_(a) can be C; and when E is CR₂, F is N and G is    NR_(1b), that is the bicyclic ring is an indazole, then J_(a) is C;-   M is selected from hydrogen, alkyl, alkenyl, cycloalkyl,    cycloalkenyl, aryl, heteroaryl, and heterocyclo other than    piperidinyl;-   M_(a) is a linker between C and M and is selected from a bond; C₁-C₅    alkylene; C₁-C₅ alkylene which includes at any position in the    chain a) a nitrogen which is substituted with alkyl, b) an    oxygen, c) a sulfur, or d) an SO₂ group; —C(R_(m) ₁ )(R_(m) ₂    )C(═O)N(R_(m) ₃ )—; —C(R_(m) ₁ )(R_(m) ₂ )S(═O)₂N(R_(m) ₃ )—;    —Oalkyl; —N(R_(m) ₃ )C(═O)C(R_(m) ₁ )(R_(m) ₂ )—; —S(═O)₂N(R_(m) ₁    )C(R_(m) ₂ )(R_(m) ₃ )—; and —N(R_(m) ₁ )C(═O)N(R_(m) ₂ )—; where    R_(m) ₁ , R_(m) ₂ and R_(m) ₃ at each occurrence are independently    selected from H and C₁-C₄ alkyl; or R_(m) ₁ and R_(m) ₂ combine to    form a C₃₋₆ carbocyclic or heterocyclic ring;-   Q is selected from    -   (i) hydrogen, halogen, nitro, cyano, hydroxy, and C₁-C₄ alkyl;        or    -   (ii) Q and R₆ are combined with the carbons to which they are        attached to form a 3- to 6-membered cycloalkyl; or    -   (iii) Q and -M_(a)-M are combined with the carbons to which they        are attached to form a 3- to 7-membered ring containing 0, 1 or        2 heteroatoms which are the same or different and are        independently selected from the group consisting of O, S, SO₂,        and

which ring may be optionally substituted with 0-2 R₃ groups or carbonyl;

-   Z is selected from alkyl, cycloalkyl, heterocyclo, aryl,    alkylsulfonyl, haloalkylsulfonyl, and heteroaryl other than    substituted or unsubstituted 4-pyridyl;-   Z_(a) is a linker between N and Z and is selected from a bond; C₁-C₅    alkylene; C₁-C₅ alkylene which includes at any position in the chain    a nitrogen which is substituted with alkyl or an SO₂ group; —C(R_(z)    ₁ )(R_(z) ₂ )C(═O)N(R_(z) ₃ )—; —C(═O)N(R_(z) ₁ )C(R_(z) ₂ )(R_(z) ₃    )—; —C(R_(z) ₁ )(R_(z) ₂ )S(═O)₂N(R_(z) ₃ )—; or —S(═O)₂N(R_(z) ₁    )C(R_(z) ₂ )(R_(z) ₃ )—; where R_(z) ₁ , R_(z) ₂ and R_(z) ₃ are    independently selected from H and C₁-C₄ alkyl;-   R₁, R_(1a) and R_(1b) are the same or different and at each    occurrence are independently selected from hydrogen, alkyl, alkenyl,    alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and    heterocyclo;-   R₂, R_(2a) and R_(2b) are the same or different and at each    occurrence are independently selected from hydrogen, halogen, alkyl,    alkenyl, alkynyl, nitro, cyano, —OR₁₀, —NR₁₀R₁₁, —C(═O)R₁₀, —CO₂R₁₀,    —C(═O)NR₁₀R₁₁, —O—C(═O)R₁₀, —NR₁₀C(═O)R₁₁, —NR₁₀C(═O)OR₁₁,    —NR₁₀C(S)OR₁₁, —S(═O)_(p)R₁₂, —NR₁₀SO₂R₁₂, —SO₂NR₁₀R₁₁, cycloalkyl,    cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl;-   R₃ at each occurrence is independently selected from hydrogen,    halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR₁₃, —NR₁₃R₁₄,    —C(═O)R₁₃, —CO₂R₁₃, —C(═O)NR₁₃R₁₄, —O—C(═O)R₁₃, —NR₁₃C(═O)R₁₄,    —NR₁₃C(═O )OR₁₄, —NR₁₃C(S)OR₁₄, —S(═O)_(p)R₁₅,    —NR₁₃SO₂R₁₅, —SO₂NR₁₃R₁₄, cycloalkyl, cycloalkenyl, cycloalkynyl,    heterocyclo, aryl, and heteroaryl;-   R₄ is selected from hydrogen, alkyl, halogen, and C₁-C₄ alkoxy;-   R₆ is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl,    nitro, cyano, —OR₁₆, —NR₁₆R₁₇, —C(═O)R₁₇, —CO₂R₁₇, —C(═O)NR₁₆R₁₇,    —O—C(═O)R₁₆, —NR₁₆C(═O)R₁₇, —NR₁₆C(═O)OR₁₇, —NR₁₆C(═S)OR₁₇,    —S(═O)_(p)R₁₈, —NR₁₆SO₂R₁₈, —SO₂NR₁₆R₁₇, cycloalkyl, cycloalkenyl,    heterocyclo, aryl, and heteroaryl;-   R₇ is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl,    nitro, cyano, —OR₁₉, —NR₁₉R₂₀, —C(═O)R₁₉, —CO₂R₁₉, —C(═O)NR₁₉R₂₀,    —O—C(═O)R₁₉, —NR₁₉C(═O)R₂₀, —NR₁₉C(═O)OR₂₀, —NR₁₉C(═S)OR₂₀,    —S(═O)_(p)R₂₁, —NR₁₉SO₂R₂₁, —SO₂NR₁₉R₂₀, cycloalkyl, cycloalkenyl,    cycloalkynyl, heterocyclo, aryl, and heteroaryl;-   or R₆ and R₇ are taken together with the carbon to which they are    attached to form a cycloalkyl, cycloalkenyl, or heterocyclo group;-   R₅, R₁₀, R₁₁, R₁₃, R₁₄, R₁₆, R₁₇, R₁₉ and R₂₀ are the same or    different and at each occurrence are independently selected from    -   (i) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        aryl, heteroaryl, and heterocyclo; or    -   (ii) with respect to R₃, R₁₃ is taken together with R₁₄; and/or        with respect to R₆, R₁₆ is taken together with R₁₇; and/or with        respect to R₇, R₁₉ is taken together with R₂₀ to form a 4- to        6-membered heteroaryl or heterocyclo ring;-   R₁₂, R₁₅, R₁₈, and R₂₁ are the same or different and are    independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, aryl, heteroaryl, or heterocyclo; and-   p is 0, 1 or 2,    provided that-   1) at least one of Q, M_(a)-M, R₆ and R₇ must be other than    hydrogen; or-   2) when Q and R₆ (and the carbons to which they are attached)    combine to form a 3- to 7-membered carbocyclic ring, then —Z_(a)-Z    cannot be C₁-C₅ alkyl; or-   3) when Q and M_(a)-M combine to form a 3- to 7-membered carbocyclic    ring, then —Z_(a)-Z cannot be C₁-C₅ alkyl; or-   4) when Z_(a) is a bond, then Z is other than

It is preferred that the group

is attached to the benzo ring portion of the bicyclic ring at the 5- or6-position; and

is a heteroaryl ring.

It is preferred that when the bicyclic ring is an indazole or indole ofthe structure

where the side chain group is linked to the 5-position and not the6-position.

The bicyclic ring system

employed in the compounds of formula I includes the following ringsystems:

wherein each of the above ring systems may optionally include an R₄group.

It is more preferred that in compounds of formula I

-   E is CR₂ or NR₁;-   F is N, NR_(1a) or CR_(2a); and-   G is NR_(1b) or CR_(2b); and-   one of J_(a) or J is optionally N.    provided that-   a) where E is NR₁, F is CR_(2a) and G is CR_(2b), or G is NR_(1b), F    is CR_(2a) and E is CR₂ so that the resulting bicyclic ring is an    indole, then R_(1a), R_(2a) and/or R_(2b) cannot be —NH₂; or-   b) where E is NR₁, F is N, and G is CR_(2b) or G is NR_(1b), F is N    and E is CR₂, so that the resulting bicyclic ring is an indazole,    then R₁, R_(1b), R₂ and R_(2a) cannot be NH₂; or-   c) when the bicyclic ring is an indazole and Q and M-M_(a) (and the    carbon to which they are attached) combine to form a 5- or    6-membered ring, then —Z_(a)-Z cannot be C₁-C₅ alkyl; or-   d) when the bicyclic ring is an indazole, Q and M-M_(a) (and the    carbon to which they are attached) cannot combine to form a    cyclohexane ring, or a cyclohexene ring or a cyclohexadiene ring; or-   e) when the bicyclic ring is an indazole and R₆ or R₇ is    independently H or C₁-C₇ alkyl, then Z_(a) cannot be (CH₂)₀₋₄.

It is preferred that when -M_(a)-M is alkyl, arylalkyl, cycloalkyl,aryl, heteroaryl, or heteroarylalkyl, the —Z_(a)-Z is other than C₁-C₇alkyl or aryl.

It is more preferred that in the compounds of formula I

In more preferred embodiments of compounds of formula I,

-   R_(1b) is H, aryl, alkyl, heterocyclo, alkylsulfonylalkyl,    heteroaryl, or hydroxyalkyloxyalkyl;-   Z_(a) is a bond;-   Z is heteroaryl, cycloalkyl, alkylsulfonyl, haloalkylsulfonyl, or    haloalkyl;-   M is aryl, alkyl, cycloalkyl, heteroaryl, arylalkyl, or    hydroxyheteroaryl;-   M_(a) is a bond or alkyl;-   Q is hydrogen or alkyl,-   or Q and M-M_(a) and the carbons to which they are attached can    combine to form a heterocyclo ring, or a cycloalkyl ring,-   or Q and R₆ and the carbons to which they are attached can combine    to form a heterocyclo ring, or a cycloalkyl ring.

In still more preferred embodiments of compounds of formula I,

-   Z_(a) is a bond;-   Z is heteroaryl substituted with one, two or three groups which are    the same or different and are independently selected from hydrogen,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, nitro, cyano, OR₁ ^(c), NR₁ ^(a)R₁    ^(b), C(═O)R₁ ^(c), CO₂R₁ ^(c), C(═O)NR₁ ^(a)R₁ ^(b), —O—C(═O)R₁    ^(c), NR₁ ^(a)C(═O)R₁ ^(b), NR₁ ^(a)C(═O)OR₁ ^(b), NR₁ ^(a)C(═S)OR₁    ^(b), S(═O)_(p) ₁ R₁ ^(c), NR₁ ^(a)SO₂R₁ ^(b), SO₂NR₁ ^(a)R₁ ^(b),    cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl; and-   R₁a, R₁ ^(b), and R₁ ^(c), are the same or different and are    independently selected from (i) hydrogen, alkyl, substituted alkyl,    alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,    cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii)    where possible R^(a) is taken together with R^(b) to form a    heteroaryl or heterocyclo ring; and-   p₁ is 0, 1 or 2.

Where Z is heteroaryl, preferred heteroaryls are selected from:

-   R^(m) and R^(n) are the same or different and at each occurrence are    independently selected from hydrogen, halogen, cycloalkyl, cyano,    haloalkyl, thioalkyl, —CO₂R^(c), —NR^(a)R^(b), —C(═O)R^(c),    —C(O)N(R^(a))(R^(b)), OR^(c), alkyl, substituted alkyl, aryl,    heteroaryl and heterocyclo;-   or R^(m) and R^(n) combine to form a 5-, 6- or 7-membered    carbocyclic, aryl, heteroaryl or heterocyclo ring which contains 0,    1, 2 or 3 hetero atoms which can be N, O, or S;-   R^(a) and R^(b) are the same or different and at each occurrence are    independently selected from hydrogen, alkyl, substituted alkyl,    C(═O)alkyl, CO₂(alkyl), SO₂alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, amino, substituted amino (NR^(a) ¹    R^(b) ¹ where R^(a) ¹ and R^(b) ¹ are independently selected from H,    alkyl or any of the R^(c) groups defined below), aryl, heteroaryl,    cycloalkenyl, heterocyclo, and cycloalkyl, provided R^(a) and R^(b)    are not both alkoxy, amino, or substituted amino, or where possible    R^(a) is taken together with R^(b) to form a heteroaryl or    heterocyclo ring;-   R^(c) is selected from hydrogen, alkyl, substituted alkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, amino,    substituted amino, heteroaryl, heterocyclo, cycloalkyl, and aryl;    and-   R^(o) is selected from alkyl, substituted alkyl, aryl, heteroaryl    and heterocyclo;-   or R^(m) and R^(o) combine to form a 5-, 6- or 7-membered    carbocyclic, aryl, heteroaryl or heterocyclo ring which contains 0,    1, 2 or 3 hetero atoms which can be N, O or S.

In preferred embodiments of compounds of formula I of the invention,

-   E is CH;-   F is N;-   G is NR_(1b);-   R_(1b) is haloalkylaryl, haloaryl, haloalkylalkyl(halo)aryl,    alkoxyaryl, alkoxycarbonylaryl, H, hydroxyalkyl, heterocyclo,    alkylheterocyclo, alkylsulfonylalkyl, alkyl, heteroaryl,    hydroxyaryl, alkoxyalkyl, arylalkyl, cycloalkyl, alkoxycarbonylaryl,    or carboxyaryl;-   Z is heteroaryl, alkoxycarbonylheteroaryl, alkylheteroaryl,    cycloalkyl, aminoheteroaryl, cycloheteroaryl, cycloalkylheteroaryl,    hydroxyheteroaryl, alkylthioheteroaryl, dialkylheteroaryl,    haloalkylheteroaryl, haloheteroaryl, hydroxycycloalkyl,    aminocycloalkyl, alkylcarbonylaminocycloalkyl, alkylsulfonyl,    haloalkylsulfonyl, alkyl, or haloalkyl;-   Z_(a) is a bond;-   M is alkyl, aryl, cycloalkyl, heteroayl, arylalkyl, heterocyclo,    alkylarylalkyl, alkylaryl, or haloaryl;-   M_(a) is a bond;-   Q is H or alkyl, or-   Q and R₆ and the carbons to which they are attached can be combined    to form

-   Q and M-M_(a) and the carbons to which they are attached can be    combined to form

In more preferred embodiments of the compounds of formula I of theinvention,

-   E is CH or NR₁;-   F is N, NR_(1a) or CR_(2a); and-   G is NR_(1b) or CR_(2b);-   R₁ is CH, H or —C═O;-   R_(1a) is H,

-   R_(2a) is

-   R_(1b) is

-   —Z_(a)-Z is

-   -M_(a)M is CH₃,

-   Q is H or CH₃; or-   Q and R₆ together with the carbons to which they are attached can be    combined to form

-   Q and M-M_(a) together with the carbons to which they are attached    can be combined to form

-   R₄ is H or CH₃;-   R₆ is CH₃, C₂H₅, C₃H₇, i-C₃H₇, or H or is combined with Q as    described above;-   R₇ is CH₃, C₂H₅, C₃H₇, i-C₃H₇, C₆H₅, —CH₂C₆H₅,

—CH₂OC(═O)CH₃, —CH₂OH, or H.

Most preferred are compounds of the structure

where R_(1b) is p-F—C₆H₄—;

-   R₄ is H or CH₃;-   R₆ is H or CH₃;-   R₇ is H or CH₃;-   Q is H;-   M is C₆H₅;-   M_(a) is a bond;-   Z is

-   Z_(a) is a bond, or a pharmaceutically acceptable salt thereof.

The following compounds represent preferred embodiments of the invention

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, there is providedpharmaceutical compositions useful in treating endocrine disorders,rheumatic disorders, collagen diseases, dermatologic disease, allergicdisease, ophthalmic disease, respiratory disease, hematologic disease,gastrointestinal disease, metabolic disease, inflammatory disease,autoimmune disease, and neoplastic disease, as well as other uses asdescribed herein, which including a therapeutically effective amount(depending upon use) of a compound of formula (I) of the invention and apharmaceutically acceptable carrier.

In still another embodiment, the present invention provides a method oftreating endocrine disorders, rheumatic disorders, collagen diseases,dermatologic disease, allergic disease, ophthalmic disease, respiratorydisease, hematologic disease, gastrointestinal disease, inflammatorydisease, immune disease, metabolic disease (diabetes and/or obesity),and neoplastic disease. A disease associated with the expression productof a gene whose transcription is stimulated or repressed byglucocorticoid receptors, or a disease associated with AP-1- and/orNF-κB-induced transcription, or a disease associated with AP-1 and/orNF-κB dependent gene expression, wherein the disease is associated withthe expression of a gene under the regulatory control of AP-1 and/orNF-κB (particularly AP-1), including inflammatory and immune diseasesand disorders as described hereinafter, which includes the step ofadministering a therapeutically effective amount of a compound offormula (I) of the invention to a patient.

Another embodiment of the present invention involves a method fortreating a disease or disorder associated with the expression product ofa gene whose transcription is stimulated or repressed by glucocorticoidreceptors, or a method of treating a disease or disorder associated withAP-1- and/or NF-κB- (particularly AP-1-) induced transcription, or amethod for treating a disease or disorder associated with AP-1 and/orNF-κB (particularly AP-1) dependent gene expression, wherein the diseaseis associated with the expression of a gene under the regulatory controlof AP-1 and/or NF-κβ (particularly AP-1), such as inflammatory andimmune disorders, cancer and tumor disorders, such as solid tumors,lymphomas and leukemia, and fungal infections such as mycosis fungoides.

The term “disease associated with GR transactivation,” as used herein,refers to a disease associated with the transcription product of a genewhose transcription is transactivated by a GR. Such diseases include,but are not limited to: osteoporosis, diabetes (including Type IIdiabetes), obesity, glaucoma, muscle loss, facial swelling, personalitychanges, hypertension, obesity, depression, and AIDS, the condition ofwound healing, primary or secondary andrenocortical insufficiency, andAddison's disease.

The term “treat”, “treating”, or “treatment,” in all grammatical forms,as used herein refers to the prevention, reduction, or amelioration,partial or complete alleviation, or cure of a disease, disorder, orcondition, wherein prevention indicates treatment of a person at riskfor developing such a disease, disorder or condition.

The terms “glucocorticoid receptor” and “GR,” as used herein, refereither to a member of the nuclear hormone receptor (“NHR”) family oftranscription factors which bind glucocorticoids and either stimulate orrepress transcription, or to GR-beta.

These terms, as used herein, refer to glucocorticoid receptor from anysource, including but not limited to: human glucocorticoid receptor asdisclosed in Weinberger et al., Science, 228:740-742 (1985), and inWeinberger, et al., Nature, 318:670-672 (1986); rat glucocorticoidreceptor as disclosed in Miesfeld, R., Nature, 312:779-781 (1985); mouseglucocorticoid receptor as disclosed in Danielson, M. et al., EMBO J.,5:2513 (1986); sheep glucocorticoid receptor as disclosed in Yang, K. etal., J. Mol. Endocrinol., 8:173-180 (1992); marmoset glucocorticoidreceptor as disclosed in Brandon, D. D. et al., J. Mol. Endocrinol.,7:89-96 (1991); and human GR-beta as disclosed in Hollenberg, S. M. etal., Nature, 318:635 (1985); Bamberger, C. M. et al., J. Clin. Invest.,95:2435 (1995).

The term, “disease or disorder associated with AP-1 and/or NF-κB” asused herein, refers to a disease associated with the expression productof a gene under the regulatory control of AP-1 and/or NF-κB. Suchdiseases include, but are not limited to: inflammatory and immunediseases and disorders; cancer and tumor disorders, such as solidtumors, lymphomas and leukemia; and fungal infections such as mycosisfungoides.

The term “inflammatory or immune associated diseases or disorders” isused herein to encompass any condition, disease, or disorder that has aninflammatory or immune component, including, but not limited to, each ofthe following conditions: transplant rejection (e.g., kidney, liver,heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, smallbowel, skin allografts, skin homografts (such as employed in burntreatment), heart valve xenografts, serum sickness, and graft vs. hostdisease, autoimmune diseases, such as rheumatoid arthritis, psoriaticarthritis, multiple sclerosis, Type I diabetes, juvenile diabetes,asthma, inflammatory bowel disease (such as Crohn's disease andulcerative colitis), pyoderma gangrenum, lupus (systemic lupuserythematosis), myasthenia gravis, psoriasis, dermatitis,dermatomyositis; eczema, seborrhea, pulmonary inflammation, eye uveitis,hepatitis, Graves' disease, Hashimoto's thyroiditis, autoimmunethyroiditis, Behcet's or Sjorgren's syndrome (dry eyes/mouth),pernicious or immunohaemolytic anaemia, atherosclerosis, Addison'sdisease (autoimmune disease of the adrenal glands), idiopathic adrenalinsufficiency, autoimmune polyglandular disease (also known asautoimmune polyglandular syndrome), glomerulonephritis, scleroderma,morphea, lichen planus, vitiligo (depigmentation of the skin), alopeciaareata, autoimmune alopecia, autoimmune hypopituitarism, Guillain-Barresyndrome, and alveolitis; T-cell mediated hypersensitivity diseases,including contact hypersensitivity, delayed-type hypersensitivity,contact dermatitis (including that due to poison ivy), uticaria, skinallergies, respiratory allergies (hayfever, allergic rhinitis) andgluten-sensitive enteropathy (Celiac disease); inflammatory diseasessuch as osteoarthritis, acute pancreatitis, chronic pancreatitis, acuterespiratory distress syndrome, Sezary's syndrome and vascular diseaseswhich have an inflammatory and or a proliferatory component such asrestenosis, stenosis and atherosclerosis. Inflammatory or immuneassociated diseases or disorders also includes, but is not limited to:endocrine disorders, rheumatic disorders, collagen diseases,dermatologic disease, allergic disease, ophthalmic disease, respiratorydisease, hematologic disease, gastrointestinal disease, inflammatorydisease, autoimmune disease, congenital adrenal hyperplasia,nonsuppurative thyroiditis, hypercalcemia associated with cancer,juvenile rheumatoid arthritis, Ankylosing spondylitis, acute andsubacute bursitis, acute nonspecific tenosynovitis, acute goutyarthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis,epicondylitis, acute rheumatic carditis, pemphigus, bullous dermatitisherpetiformis, severe erythema multiforme, exfoliative dermatitis,seborrheic dermatitis, seasonal or perennial allergic rhinitis,bronchial asthma, atopic dermatitis, drug hypersensitivity reactions,allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritisand iridocyclitis, chorioretinitis, optic neuritis, symptomaticsarcoidosis, fulminating or disseminated pulmonary tuberculosischemotherapy, idiopathic thrombocytopenic purpura in adults, secondarythrombocytopenia in adults, acquired (autoimmune) hemolytic anemia,leukemias and lymphomas in adults, acute leukemia of childhood, regionalenteritis, autoimmune vasculitis, chronic obstructive pulmonary disease,solid organ transplant rejection and sepsis.

Accordingly, one embodiment of the present invention is a method oftreating a disease or disorder selected from an endocrine disorder,rheumatic disorder, collagen disease, dermatologic disease, allergicdisease, ophthalmic disease, respiratory disease, hematologic disease,gastrointestinal disease, inflammatory disease, immune disease,neoplastic disease and metabolic disease, which includes the step ofadministering to a patient in need of treatment, a therapeuticallyeffective amount of a compound as defined in Claim 1.

Metabolic diseases to be treated in accordance with the method of theinvention can include Type II diabetes and obesity. Type I diabetes andjuvenile diabetes may also be considered as metabolic diseases to betreated in accordance with the method of the invention.

In a preferred embodiment of the invention, the disease to be treated isan inflammatory or immune associated disease or disorder as definedhereinbefore.

In a preferable embodiment the disease or disorder is an inflammatory orautoimmune disease selected from transplant rejection of kidney, liver,heart, lung, pancreas, bone marrow, cornea, small bowel, skinallografts, skin homografts, heart valve xenograft, serum sickness, andgraft vs. host disease, rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, asthma, inflammatory bowel disease, Crohn's disease,ulcerative colitis, pyoderma gangrenum, systemic lupus erythematosis,myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema,seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Graves'disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's orSjorgren's syndrome, pernicious or immunohaemolytic anaemia,atherosclerosis, Addison's disease, idiopathic adrenal insufficiency,autoimmune polyglandular disease, glomerulonephritis, scleroderma,morphea, lichen planus, vitiligo, alopecia areata, autoimmune alopecia,autoimmune hypopituitarism, Guillain-Barre syndrome, and alveolitis;contact hypersensitivity, delayed-type hypersensitivity, contactdermatitis, uticaria, skin allergies, respiratory allergies, hayfever,allergic rhinitis and gluten-sensitive enteropathy, osteoarthritis,acute pancreatitis, chronic pancreatitis, acute respiratory distresssyndrome, Sezary's syndrome, restenosis, stenosis and atherosclerosis,congenital adrenal hyperplasia, nonsuppurative thyroiditis,hypercalcemia associated with cancer, juvenile rheumatoid arthritis,Ankylosing spondylitis, acute and subacute bursitis, acute nonspecifictenosynovitis, acute gouty arthritis, post-traumatic osteoarthritis,synovitis of osteoarthritis, epicondylitis, acute rheumatic carditis,pemphigus, bullous dermatitis herpetitformis, severe erythemamultiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal orperennial allergic rhinitis, bronchial asthma, contact dermatitis,atopic dermatitis, drug hypersensitivity reactions, allergicconjunctivitis, keratitis, herpes zoster ophthalmicus, iritis andiridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis,fulminating or disseminated pulmonary tuberculosis chemotherapy,idiopathic thrombocytopenic purpura in adults, secondarythrombocytopenia in adults, acquired (autoimmune) hemolytic anemia,leukemias and lymphomas in adults, acute leukemia of childhood, regionalenteritis, autoimmune vasculitis, sepsis, and chronic obstructivepulmonary disease.

In an even more preferable embodiment, the disease or disorder isselected from transplant rejection, rheumatoid arthritis, psoriaticarthritis, multiple sclerosis, asthma, inflammatory bowel disease,systemic lupus, erythematosis, and psoriasis.

In addition, in accordance with the present invention a method oftreating a disease associated with AP-1-induced and/or NF-κB-inducedtranscription (particularly AP-1-induced transcription) is providedwherein a compound of formula (I) of the invention is administered to apatient at risk of developing the disease in a therapeutically effectiveamount to induce NHR transrepression of the AP-1-induced and/orNF-κB-induced transcription (particularly AP-1-induced transcription),thereby treating the disease.

Other therapeutic agents, such as those described hereafter, may beemployed with the compounds of the invention in the present methods. Inthe methods of the present invention, such other therapeutic agent(s)may be administered prior to, simultaneously with or following theadministration of the compound(s) of the present invention.

In a particular embodiment, the compounds of the present invention areuseful for the treatment of the aforementioned exemplary disordersirrespective of their etiology, for example, for the treatment oftransplant rejection, rheumatoid arthritis, inflammatory bowel disease,and viral infections.

In still another embodiment, pharmaceutical combinations arecontemplated comprising a compound as defined in Claim 1, an enantiomer,diastereomer, or tautomer thereof, or a prodrug ester thereof, or apharmaceutically-acceptable salt thereof, and an immunosuppressant, ananticancer agent, an anti-viral agent, an anti-inflammatory agent, ananti-fungal agent, an anti-biotic, an anti-vascular hyperproliferationagent, an anti-depressant agent, a lipid-lowering agent, a lipidmodulating agent, an antidiabetic agent, an anti-obesity agent, anantihypertensive agent, a platelet aggregation inhibitor, and/or anantiosteoporosis agent, wherein the antidiabetic agent is 1, 2, 3 ormore of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γagonist, a PPAR α/γ dual agonist, an SGLT2 inhibitor, a DP4 inhibitor,an aP2 inhibitor, an insulin sensitizer, a glucagon-like peptide-1(GLP-1), insulin and/or a meglitinide, wherein the anti-obesity agent isa beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (anddopamine) reuptake inhibitor, a thyroid receptor agonist, an aP2inhibitor and/or an anorectic agent, wherein the lipid-lowering agent isan MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetaseinhibitor, a fabric acid derivative, an upregulator of LDL receptoractivity, a lipoxygenase inhibitor, or an ACAT inhibitor, wherein theantihypertensive agent is an ACE inhibitor, angiotensin II receptorantagonist, NEP/ACE inhibitor, calcium channel blocker and/orβ-adrenergic blocker.

More preferred combinations are those wherein the antidiabetic agent is1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride,glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone,troglitazone, rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501,NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide,KAD1129, AR-H039242, GW-409544, KRP297, AC2993, LY315902, P32/98 and/orNVP-DPP-728A, wherein the anti-obesity agent is orlistat, ATL-962,AJ9677, L750355, CP331648, sibutramine, topiramate, axokine,dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol,wherein the lipid-lowering agent is pravastatin, lovastatin,simvastatin, atorvastatin, cerivastatin, fluvastatin, itavastatin,visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962,MD-700, cholestagel, niacin and/or LY295427, wherein theantihypertensive agent is an ACE inhibitor which is captopril,fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril,ramipril or moexipril; an NEP/ACE inhibitor which is omapatrilat,[S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat) or CGS 30440;

-   an angiotensin II receptor antagonist which is irbesartan, losartan    or valsartan;-   amlodipine besylate, prazosin HCl, verapamil, nifedipine, nadolol,    propranolol, carvedilol, or clonidine HCl, wherein the platelet    aggregation inhibitor is aspirin, clopidogrel, ticlopidine,    dipyridamole or ifetroban;-   the immunosuppressant is a cyclosporin, mycophenolate,    interferon-beta, deoxyspergolin, FK-506 or Ant.-IL-2;-   the anti-cancer agent is azathiprine, 5-fluorouracel,    cyclophosphamide, cisplatin, methotrexate, thiotepa, or carboplatin;-   the anti-viral agent is abacavir, aciclovir, ganciclovir, zidanocin,    or vidarabine; and-   the antiinflammatory drug is ibuprofen, celecoxib, rofecoxib,    aspirin, naproxen, ketoprofen, diclofenac sodium, indomethacin,    piroxicam, prednisone, dexamethasone, hydrocortisone, or    triamcinolone diacetate.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects and embodiments ofthe invention noted herein. It is understood that any and allembodiments may be taken in conjunction with any other embodiment todescribe additional embodiments of the present invention. Furthermore,any elements of an embodiment are meant to be combined with any and allother elements from any of the embodiments to describe additionalembodiments.

METHODS OF PREPARATION

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry.General synthetic schemes for preparing compounds of the presentinvention are described below. These schemes are illustrative and arenot meant to limit the possible techniques one skilled in the art mayuse to prepare the compounds disclosed herein. Different methods toprepare the compounds of the present invention will be evident to thoseskilled in the art. Additionally, the various steps in the synthesis maybe performed in an alternate sequence in order to give the desiredcompound or compounds. Examples of compounds of the present inventionprepared by methods described in the general schemes are given in thepreparations and examples section set out hereinafter. Example compoundsare typically prepared as racemic mixtures. Preparation of homochiralexamples may be carried out by techniques known to one skilled in theart. For example, homochiral compounds may be prepared by separation ofracemic products by chiral phase preparative HPLC. Alternatively, theexample compounds may be prepared by methods known to giveenantiomerically enriched products. These include, but are not limitedto, the incorporation of chiral auxiliary functionalities into racemicintermediates which serve to control the diastereoselectivity oftransformations, providing enantio-enriched products upon cleavage ofthe chiral auxiliary.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Additionally, the various steps in the synthesis may be performed in analternate sequence in order to give the desired compound or compounds.Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the preparations andexamples section set out hereinafter. Example compounds are typicallyprepared as racemic mixtures. Preparation of homochiral examples may becarried out by techniques known to one skilled in the art. For example,homochiral compounds may be prepared by separation of racemic productsby chiral phase preparative HPLC. Alternatively, the example compoundsmay be prepared by methods known to give enantiomerically enrichedproducts. These include, but are not limited to, the incorporation ofchiral auxiliary functionalities into racemic intermediates which serveto control the diastereoselectivity of transformations, providingenantio-enriched products upon cleavage of the chiral auxiliary.

As shown in Scheme 1, intermediates on the path to compounds of FormulaI may be synthesized from benzannulated heterocyclic aldehydes II whichare reported in the literature or synthesized by one skilled in the art.Grignard or aryl(alkyl)lithium reagents add to give alcohol III. Thiscompound may be reacted with silyl ketene acetals in the presence ofTiCl₄ to yield the alkylated product IV, and finally hydrolyzed (e.g.,NaOH, DMSO, MeOH) to acid V. Alternatively, compound III can be oxidizedto the ketone/aldehyde VII using a suitable oxidant (e.g., Dess-Martinperiodinane) and then reacted with various enolates (the aldol reaction)or with silyl ketene acetals in the presence of a Lewis acid such asBF₃OEt₂ (the Mukaiyama aldol reaction) to give compound VIII. CompoundVIII may be readily deoxygenated using trifluoroacetic acid in thepresence of triethylsilane (or via a Barton deoxygenation: Org. Lett.,4:39-42 (2002)) to give compound IV or hydrolyzed to form compound IX.By starting with benzannulated heterocyclic ester VI, one can use theWeinreb amidation procedure (Me₃Al, MeONHMe) followed by organometallicaddition to also synthesize intermediate VII. In the cases whereM-M_(a)- and Q are the same (or form a symmetrical ring), a parallelroute can be employed by using two equivalents of theM-M_(a)-organometallic reagent to form alcohol X (also accessible fromVII) that undergoes TiCl₄-mediated alkylation with silyl ketene acetalsfollowed by hydrolysis as before to yield acid XII where Q and M-M_(a)may be the same or different.

Many of the heterocyclic substituents of intermediates in Scheme 1 canbe synthesized by one skilled in the art of organic synthesis. Otherfunctional group manipulations that complement those in Scheme 1 areshown in Schemes 2 and 3.

Scheme 2 shows how phenolic intermediates such as XIII can be convertedto a triflate followed by palladium-mediated carbonylation to form esterVI. The ester functionality can be transposed into an aldehyde (compoundII) or other groups shown in Scheme 1.

Scheme 3 shows how an unsubstituted heterocycle XIV can befunctionalized to intermediate VII using a modification of the classicalFriedel-Crafts acylation (see J. Med. Chem., 26:806 (1983)).

A more specific implementation of the synthetic scheme outlined inScheme 1 is shown in Scheme 4 using indazoles as a representativeheterocycle. Starting aniline XV is converted to(1H-indazol-5-yl)methanol XVI-A using standard literature procedures(Sun et al., J. Org. Chem., 62:5627-5629 (1997)). Functionalization ofthe indazole N-1 nitrogen (or N-2 nitrogen, not shown) via a Buchwaldarylation procedure (J. Org. Chem., 69:5578-5587 (2004); J. Am. Chem.Soc., 123:7727-7729 (2001)) can be effected at multiple points duringthe synthetic scheme to ultimately provide compounds of Formula I.Alternatively, alkylation of the indazole N-1 nitrogen (or N-2 nitrogen)using a base and an R₁ alkylator (herein defined as a diverseelectrophilic reagent that may undergo an SN2 reaction, e.g., anon-tertiary alkyl iodide or bromide, epoxide, etc.) in a suitablesolvent may also provide intermediates in route to compounds of FormulaI.

Thus, compound XVI-A may be functionalized using a Buchwald arylationprocedure or alkylated to give compound XVI-B. Oxidation of XVI-A/Busing a suitable oxidant (e.g., Dess-Martin reagent) followed byaddition of a Grignard reagent or aryl/alkyllithium reagent providesXVII-A/B, respectively. XVII-A can be converted at this stage to XVII-Busing the Buchwald arylation procedure or alkylated and XVII-A/B can bereacted with silyl ketene acetals in the presence of TiCl₄ to yieldproducts XVIII-A/B. Again, XVIII-A may be optionally converted toXVIII-B at this point using the Buchwald procedure or alkylation.XVIII-A/B can then be hydrolyzed to XIX-A/B which in turn are convertedto amides of Formula I using coupling conditions described below inScheme 8. Compound XIX-A can be converted to compounds of Formula I(where R₁=H) which in turn can be further functionalized using theBuchwald arylation procedure or alkylation.

A complementary route to Scheme 1 for making precursors to Formula I isshown in Scheme 5. Ketone/aldehyde VII can be homologated using theHomer-Wadsworth-Emmons procedure to make α,β-unsaturated ester XX whichcan be hydrogenated under palladium catalysis (to form XXI) and thenhydrolyzed to form compound XXII (same as compound V, where R₆, R₇=H.).Alternatively, intermediate XX can be treated with a cuprate reagentcontaining the Q diversity to give XXIII and then hydrolyzed to XXIV.Alkylation of compound XXIII using LDA followed by an R₆ electrophile(such as an alkyl iodide) provides XXVI after hydrolysis. IntermediateXXV can be alkylated again using an R₇ electrophile to provide acid XIIafter hydrolysis.

Another means of making intermediates on route to Formula I compounds isshown in Scheme 6. Metal-halogen exchange of compound XXVII using analkyllithium reagent followed by treatment with a ketone or aldehydeprovides compound X which can be transposed to compound XII aspreviously described in Scheme 1.

Scheme 7 illustrates a synthetic method to make a precursor of Formula Iwherein Q and R₆ form a ring (cyclopropyl shown here). Treatment ofcompound VII with MeMgBr yields a tertiary alcohol which can beeliminated in hot glacial acetic acid to olefin XXVIII.Rhodium-carbenoid addition to this olefin provides a cyclopropyl esterwhich can be hydrolyzed to give acid XXIX.

The synthetic Schemes 1 to 7 above detail synthetic sequences that makecarboxylic acids-the penultimate precursor to compounds of Formula I.The final step involves converting the carboxylic acid to an amide asshown in Scheme 8 for which there are many methods in the literature(Humphrey, Chem. Rev., 97:2243-2266 (1997)). Preferred methods in thisinvention involve activation of the acid to an intermediate acidfluoride using cyanuric fluoride followed by heating with an appropriateamine nucleophile. Another preferred method is conversion of the acid toan intermediate “active” ester (such as an HOBt or an HOAt ester) usingthe carbodiimide EDC, HOBt (or HOAt), and Et₃N in a suitable solventsuch as DMF or NMP followed by heating with the amine nucleophile.

Protecting Groups for the Heterocyclic Core

It should be understood that protecting groups may be utilized asappropriate throughout synthetic Schemes 1 to 8 above. Common protectinggroups for amine-containing heterocycles (where E, F, or G in Formula Iare nitrogen, e.g., indole, indazole, benzimidazole, etc.) are ureas,sulfonamides, carbamates, and alkyl groups (such as benzyl). Thejudicious use of protecting groups is known to one skilled in the artand is described in Greene and Wuts, Protecting Groups in OrganicSynthesis, 3rd Ed. (1999).

DEFINITIONS

The following are definitions of terms used in this specification andappended claims. The initial definition provided for a group or termherein applies to that group or term throughout the specification andclaims, individually or as part of another group, unless otherwiseindicated.

The term “alkyl” alone or as part of another group refers to straight orbranched chain hydrocarbon groups having 1 to 12 carbon atoms,preferably 1 to 8 carbon atoms. Lower alkyl groups, that is, alkylgroups of 1 to 4 carbon atoms, are most preferred. When numbers appearin a subscript after the symbol “C”, the subscript defines with morespecificity the number of carbon atoms that a particular group maycontain. For example, “C₁₋₆alkyl” refers to straight and branched chainalkyl groups with one to six carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and so forth. Thesubscript “0” refers to a bond. Thus, the term hydroxy(C₀₋₂)alkyl or(C₀₋₂)hydroxyalkyl includes hydroxy, hydroxymethyl and hydroxyethyl.

“Alkyl” includes “unsubstituted” and “substituted alkyl” where the alkylmay be substituted with any of the substituents for substituted alkylset out below.

The term “substituted alkyl” refers to an alkyl group as defined abovehaving one, two, or three substituents independently selected from thegroup consisting of halo (e.g., trifluoromethyl), alkenyl, substitutedalkenyl, alkynyl, nitro, cyano, oxo (═O), OR_(a), SR_(a), (═S),—NR_(a)R_(b), —N(alkyl)₃ ¹, —NR_(a)SO₂, —NR_(a)SO₂R_(c), —SO₂R_(c),—SO₂NR_(a)R_(b), —SO₂NR_(a)C(═O)R_(b), SO₃H, —PO(OH)₂, —C(═O)R_(a),—CO₂R_(a), —C(═O)NR_(a)R_(b), —C(═O)(C₁₋₄alkylene)NR_(a)R_(b),—C(═O)NR_(a)(SO₂)R_(b), —CO₂(C₁₋₄alkylene)NR_(a)R_(b), —CH₂OC(═O)alkyl,—NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b), —NR_(a)(C₁₋₄alkylene)CO₂R_(b),═N—OH, ═N—O-alkyl, aryl, cycloalkyl, heterocyclo, and/or heteroaryl,wherein R_(a) and R_(b) are the same or different and are independentlyselected from hydrogen, alkyl, alkenyl, CO₂H, CO₂(alkyl),C₃₋₇cycloalkyl, phenyl, benzyl, phenylethyl, naphthyl, a four to sevenmembered heterocyclo, or a five to six membered heteroaryl, or whenattached to the same nitrogen atom may join to form a heterocyclo orheteroaryl, and R_(c) is selected from same groups as R_(a) and R_(b)but is not hydrogen. Each group R_(a) and R_(b) when other thanhydrogen, and each R_(c) group optionally has up to three furthersubstituents attached at any available carbon or nitrogen atom of R_(a),R_(b), and/or R_(c), said substituent(s) being the same or different andare independently selected from the group consisting of (C₁₋₆)alkyl,(C₂₋₆)alkenyl, hydroxy, halogen, cyano, nitro, CF₃, O(C₁₋₆alkyl), OCF₃,C(═O)H, C(═O)(C₁₋₆alkyl), CO₂H, CO₂(C₁₋₆alkyl), NHCO₂(C₁₋₆alkyl),—S(C₁₋₆alkyl), —NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)₂, N(CH₃)₃ ⁺,SO₂(C₁₋₆alkyl), —NHC(═O)alkyl, C(═O)(C₁₋₄alkylene)NH₂,C(═O)(C₁₋₄alkylene)NH(alkyl), C(═O)(C₁₋₄alkylene)N(C₁₋₄alkyl)₂,C₃₋₇cycloalkyl, phenyl, benzyl, phenylethyl, phenyloxy, benzyloxy,naphthyl, a four to seven membered heterocyclo, or a five to sixmembered heteroaryl. When a substituted alkyl is substituted with anaryl, heterocyclo, cycloalkyl, or heteroaryl group, said ringed systemsare as defined below and thus may have zero, one, two, or threesubstituents, also as defined below and/or as defined for substitutedalkyl.

One skilled in the field will understand that, when the designation“CO₂” is used herein, this is intended to refer to the group

When the term “alkyl” is used together with another group, such as in“arylalkyl”, this conjunction defines with more specificity at least oneof the substituents that the substituted alkyl will contain. Forexample, “arylalkyl” refers to a substituted alkyl group as definedabove where at least one of the substituents is an aryl, such as benzyl.Thus, the term aryl(C₀₋₄)alkyl includes a substituted lower alkyl havingat least one aryl substituent and also includes an aryl directly bondedto another group, i.e., aryl(C₀)alkyl.

The term “alkenyl” (which includes unsubstituted or substituted alkenyl)alone or as part of another group refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms and at least one doublebond. Alkenyl groups of 2 to 6 carbon atoms and having one double bondare most preferred.

The term “alkynyl” (which includes unsubstituted or substituted alkynyl)alone or as part of another group refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms and at least one triplebond. Alkynyl groups of 2 to 6 carbon atoms and having one triple bondare most preferred.

The term “alkylene” (which includes unsubstituted or substitutedalkylene) alone or as part of another group refers to bivalent straightor branched chain hydrocarbon groups having 1 to 12 carbon atoms,preferably 1 to 8 carbon atoms, e.g., {—CH₂—}_(n), wherein n is 1 to 12,preferably 1-8. Lower alkylene groups, that is, alkylene groups of 1 to4 carbon atoms, are most preferred. The terms “alkenylene” and“alkynylene” refer to bivalent radicals of alkenyl and alkynyl groups,respectively, as defined above.

When reference is made to a substituted alkenyl, alkynyl, alkylene,alkenylene, or alkynylene group, these groups are substituted with oneto three substituents as defined above for substituted alkyl groups.

The term “heteroalkylene” (which includes unsubstituted and “substitutedheteroalkylene”) alone or as part of another group is used herein torefer to saturated and unsaturated bivalent straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 8 carbonatoms, wherein one or two carbon atoms in the straight chain arereplaced by heteroatom(s) selected from —O—, —S—, —S(═O)—, —SO₂—, —NH—,and —NHSO₂—. Thus, the term “heteroalkylene” includes bivalent alkoxy,thioalkyl, and aminoalkyl groups, as defined below, as well as alkyleneand alkenylene groups having a combination of heteroatoms in the alkylchain. As an illustration, a “heteroalkylene” herein may comprise groupssuch as —S—(CH₂)₁₋₅NH—CH₂—, —O—(CH₂)₁₋₅S(═O)—CH₂—, —NHSO₂—CH₂—,—CH₂—NH—, and so forth. Preferably, a heteroalkylene does not have twoadjacent atoms simultaneously selected from —O— and —S—. When asubscript is used with the term heteroalkylene, e.g., as inC₂₋₃heteroalkylene, the subscript refers to the number of carbon atomsin the group in addition to heteroatoms. Thus, for example, aC₁₋₂heteroalkylene may include groups such as —NH—CH₂—, —CH₂—NH—CH₂—,—CH₂—CH₂—NH—, —S—CH₂—, —CH₂—S—CH₂—, —O—CH₂—NH—CH₂—, CH₂—O—CH₂ and soforth.

The term “substituted heteroalkylene” refers to a heteroalkylene groupas defined above wherein at least one of the nitrogen or carbon atoms inthe heteroalkylene chain is bonded to (or substituted with) a groupother than hydrogen. Carbon atoms in the heteroalkylene chain may besubstituted with a group selected from those recited above forsubstituted alkyl groups, or with a further alkyl or substituted alkylgroup. Nitrogen atoms of the heteroalkylene chain may be substitutedwith a group selected from alkyl, alkenyl, alkynyl, cyano, orA₁-Q-A₂-R_(h), wherein A₁ is a bond, C₁₋₂alkylene, or C₂₋₃alkenylene; Qis a bond, —C(═O)—, —C(═O)NR_(d)—, —C(═S)NR_(d)—, —SO₂—, —SO₂NR_(d)—,—CO₂—, or —NR_(d)CO₂—; A₂ is a bond, C₁₋₃alkylene, C₂₋₃alkenylene,—C₁₋₄alkylene-NR_(d)—, —C₁₋₄alkylene-NR_(d)C(═O)—, —C₁₋₄alkylene-S—,—C₁₋₄alkylene-SO₂—, or —C₁₋₄alkylene-O—, wherein said A₂ alkylene groupsare branched or straight chain and optionally substituted as definedherein for substituted alkylene; R_(h) is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclo, orcycloalkyl; and R_(d) is selected from hydrogen, alkyl, and substitutedalkyl, as defined herein, provided, however, that for a substitutedheteroalkylene R_(h) is not hydrogen when A₁, Q and A₂ are each bonds.When R_(h) is aryl, heteroaryl, cycloalkyl, or heterocyclo, these ringsare, in turn, optionally substituted with one to three groups as definedbelow in the definitions for these terms.

The term “alkoxy” refers to an unsubstituted alkyl or substituted alkylgroup as defined above having one or two oxygen atoms (—O—) in the alkylchain. For example, the term “alkoxy” includes the groups —O—C₁₋₁₂alkyl,—(C₁₋₆alkylene)-O—C₁₋₆alkyl, —(C₁₋₄alkylene-O—C₁₋₄alkylene)-O—C₁₋₄alkyl,and so forth.

The term “thioalkyl” or “alkylthio” refers to an unsubstituted alkyl orsubstituted alkyl group as defined having one or two sulfur atoms in thealkyl chain. For example, the term “thioalkyl” or “alkylthio” includesthe groups —S—C₁₋₁₂alkyl, —(S—C₁₋₆alkylene)-S—C₁₋₆alkyl, and so forth.

The terms “aminoalkyl” or “alkylamino” refer to an unsubstituted alkylor substituted alkyl group as defined above having one or two nitrogen(—NR—) atoms in the alkyl chain. For example, the term “aminoalkyl”includes the groups —NR—C₁₋₁₂alkyl, —NR—C₁₋₆alkylene-NR—C₁₋₆alkyl, etc.(where R is preferably hydrogen but may include alkyl or substitutedalkyl as defined above.) When a subscript is used with reference to analkoxy, thioalkyl or aminoalkyl, the subscript refers to the number ofcarbon atoms that the group may contain in addition to heteroatoms.Thus, for example, monovalent C₁₋₂aminoalkyl includes the groups—CH₂—NH₂, —NH—CH₃, —(CH₂)₂—NH₂, —NH—CH₂—CH₃, —CH₂—NH₂—CH₃, and—N—(CH₃)₂. A lower aminoalkyl comprises an aminoalkyl having one to fourcarbon atoms.

“Amino” refers to the group NH₂.

The term “substituted amino” alone or as part of another group refers tothe group —NR_(a)R_(b) (or other substituent groups other than R_(a) orR_(b) linked to an N atom) wherein the groups R_(a) and R_(b) or othersubstituent groups are defined above in the definition of substitutedalkyl groups.

The alkoxy, thioalkyl, or aminoalkyl groups may be monovalent orbivalent. By “monovalent” it is meant that the group has a valency(i.e., ability to combine with another group), of one, and by “bivalent”it is meant that the group has a valency of two. Thus, for example, amonovalent alkoxy includes groups such as —O—C₁₋₁₂alkyl,—C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkylene-O—C₁₋₄alkyl,whereas a bivalent alkoxy includes groups such as —O—C₁₋₁₂alkylene-,—C₁₋₆alkylene-O—C₁₋₆alkylene-,—C₁₋₄alkylene-O—C₁₋₄alkylene-O—C₁₋₄alkylene-, and so forth.

The term “carbonyl” is intended to designate the group —C(O)—.

It should be understood that the selections for alkoxy, thioalkyl, andaminoalkyl will be made by one skilled in the field to provide stablecompounds. Thus, for example, in compounds of formula I, when R₅, R₆, R₇or R₈ is attached to a nitrogen atom (N*) of ring B and is selected froman alkoxy or alkylthio group, the alkoxy and alkylthio groups will haveat least one carbon atom bonded directly to ring B (at N*), with theoxygen or sulfur atoms being at least one atom away from said nitrogenatom.

The term “acyl” alone or as part of another group refers to a carbonylgroup linked to an organic radical, more particularly, the groupC(═O)R_(e), as well as the bivalent groups —C(═O)— or —C(═O)R_(e)—,which are linked to organic radicals or a ring in compounds of formulaI. The group R_(e) can be selected from alkyl, alkenyl, alkynyl,aminoalkyl, substituted alkyl, substituted alkenyl, or substitutedalkynyl, as defined herein, or when appropriate, the correspondingbivalent group, e.g., alkylene, alkenylene, etc. Accordingly, incompounds of formula I, when it is recited that R₁ to R₈ can be “acyl,”this is intended to encompass a selection for R₁ to R₈ of —C(═O)— andalso the groups —C(═O)R_(e)— or —R_(e)C(═O)—, wherein in this instance,the group R_(e) will be selected from bivalent groups, e.g., alkylene,alkenylene, alkynylene, bivalent aminoalkyl, substituted alkylene,substituted alkenylene, or substituted alkynylene.

The term “alkoxycarbonyl” alone or as part of another group refers to acarboxy group

linked to an organic radical (CO₂R_(e)), as well as the bivalent groups—CO₂—, —CO₂R_(e)— which are linked to organic radicals in compounds offormula I, wherein R_(e) is as defined above for acyl. The organicradical to which the carboxy group is attached may be monovalent (e.g.,—CO₂-alkyl or —OC(═O)alkyl), or bivalent (e.g., —CO₂-alkylene,—OC(═O)alkylene, etc.). Accordingly, “alkoxycarbonyl,” is intended toencompass the groups —CO₂R_(e)— or —R_(e)CO₂—, wherein in this instance,the group R_(e) will be selected from bivalent groups, e.g., alkylene,alkenylene, alkynylene, bivalent aminoalkyl, substituted alkylene,substituted alkenylene, or substituted alkynylene.

The term “amide” or “amidyl” alone or as part of another group refers tothe group C(═O)NR_(a)R_(b) (or other R groups other than R_(a) or R_(b)linked to an N atom), wherein the groups R_(a) and R_(b) are defined asrecited above in the definition for substituted alkyl groups.

The term “sulfonyl” alone or as part of another group refers to asulphoxide group linked to an organic radical in compounds of formula I,more particularly, the monovalent group S(O)₁₋₂—R_(e), or the bivalentgroup —S(O)₁₋₂— linked to organic radicals in compounds of formula I.Accordingly, in compounds of formula I, “sulfonyl,” is intended toencompass —S(═O)— or —SO₂— as well as the groups —S(═O)R_(e)—,—R_(e)S(═O)—, —SO₂R_(e)—, or —R_(e)SO₂—, wherein in this instance, thegroup R_(e) will be selected from those recited above for acyl andalkoxycarbonyl groups.

The term “sulfonamidyl” alone or as part of another group refers to thegroup —S(O)₂NR_(a)R_(b) (or other R groups other than R_(a) or R_(b)linked to an N atom), wherein R_(a) and R_(b) are as defined above forsubstituted alkyl groups. Additionally, the sulfonamidyl group may bebivalent, in which case one of the groups R_(a) and R_(b) will be abond. Thus, in compounds of formula I, sulfonamidyl is intended to meanthe group —S(O)₂NR_(a)—.

The term “cycloalkyl” alone or as part of another group (which includesunsubstituted cycloalkyl and substituted cycloalkyl) refers to fullysaturated and partially unsaturated hydrocarbon rings of 3 to 15,preferably 3 to 10 carbon atoms. Accordingly, the term “cycloalkyl” isintended to include a cycloalkenyl (e.g., cyclohexenyl) ring. The term“cycloalkyl” includes monocyclic, bicyclic and tricyclic rings, suchrings having zero, one, two, or three substituents selected from thegroup consisting of halogen, trifluoromethyl, trifluoromethoxy, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, nitro, cyano,oxo (═O), OR_(a), SR_(a), (═S), —NR_(a)R_(b), —N(alkyl)₃ ⁺, —NR_(a)SO₂,—NR_(a)SO₂R_(c), —SO₂R_(c) —SO₂NR_(a)R_(b), —SO₂NR_(a)C(═O)R_(b), SO₃H,—PO(OH)₂, —C(═O)R_(a), —CO₂R_(a), —C(═O)NR_(a)R_(b),—C(═O)(C₁₋₄alkylene)NR_(a)R_(b), —C(═O)NR_(a)(SO₂)R_(b),—CO₂(C₁₋₄alkylene)NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b),—NR_(a)(C₁₋₄alkylene)CO₂R_(b), ═N—OH, ═N—O-alkyl, aryl, cycloalkyl,heterocyclo, and/or heteroaryl, wherein R_(a), R_(b) and R_(c) are asdefined above for substituted alkyl groups, and are also in turnoptionally substituted as recited above in the definition forsubstituted alkyl groups. The term “cycloalkyl” also includes such ringshaving a second ring fused thereto (e.g., including benzo, cycloalkyl,heterocyclo, or heteroaryl rings) or having a carbon-carbon bridge of 3to 4 carbon atoms. When a cycloalkyl is substituted with a further ring(or has a second ring fused thereto), said ring in turn is optionallysubstituted with one to two of (C₁₋₄alkyl, (C₂₋₄)alkenyl, halogen,hydroxy, cyano, nitro, CF₃, O(C₁₋₄alkyl), OCF₃, C(═O)H,C(═O)(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄alkyl), NHCO₂(C₁₋₄alkyl), —S(C₁₋₄alkyl),—NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, N(C₁₋₄alkyl)₃ ⁺, SO₂(C₁₋₄alkyl),C(═O)(C₁₋₄alkylene)NH₂, C(═O)(C₁₋₄alkylene)NH(alkyl), and/orC(═O)(C₁₋₄alkylene)N(C₁₋₄alkyl)₂.

Accordingly, in compounds of formula (I), the term “cycloalkyl” includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, etc., as well as the following ring systems,

and the like, which optionally may be substituted at any available atomsof the ring(s). Preferred cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl,

The term “halo” or “halogen” alone or as part of another group refers tochloro, bromo, fluoro and iodo.

The term “haloalkyl” alone or as part of another group means asubstituted alkyl having one or more halo substituents. For example,“haloalkyl” includes mono, bi, and trifluoromethyl.

The term “haloalkoxy” alone or as part of another group means an alkoxygroup having one or more halo substituents. For example, “haloalkoxy”includes OCF₃.

The term “aryl” alone or as part of another group (includesunsubstituted aryl and substituted aryl) refers to phenyl, biphenyl,1-naphthyl and 2-naphthyl. The term “aryl” includes such rings havingzero, one, two or three substituents selected from the group consistingof halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, nitro, cyano, OR_(a), SR_(a),(═S), —NR_(a)R_(b), —N(alkyl)₃ ⁺, —NR_(a)SO₂, —NR_(a)SO₂R_(c), —SO₂R_(c)—SO₂NR_(a)R_(b), —SO₂NR_(a)C(═O)R_(b), SO₃H, —PO(OH)₂, —C(═O)R_(a),—CO₂R_(a), —C(═O)NR_(a)R_(b), —C(═O)(C₁₋₄alkylene)NR_(a)R_(b),—C(═O)NR_(a)(SO₂)R_(b), —NHC(═O)NR_(a)R_(b),—CO₂(C₁₋₄alkylene)NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b),—NR_(a)(C₁₋₄alkylene)CO₂R_(b), aryl, cycloalkyl, heterocyclo, and/orheteroaryl, wherein R_(a), R_(b) and R_(c) are as defined above forsubstituted alkyl groups, and are also in turn optionally substituted asrecited above, or any of the substituents for alkyl set outhereinbefore. Additionally, two substituents attached to an aryl,particularly a phenyl group, may join to form a further ring such as afused or spiro-ring, e.g., cyclopentyl or cyclohexyl, or fusedheterocyclo or heteroaryl. When an aryl is substituted with a furtherring (or has a second ring fused thereto), said ring in turn isoptionally substituted with one to four, preferably one or two of(C₁₋₄)alkyl, (C₂₋₄)alkenyl, halogen, hydroxy, cyano, nitro, CF₃,O(C₁₋₄alkyl), OCF₃, C(═O)H, C(═O)(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄alkyl),NHCO₂(C₁₋₄alkyl), —S(C₁₋₄alkyl), —NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,N(C₁₋₄alkyl)₃ ⁺, C(═O)NH₂, SO₂(C₁₋₄alkyl), C(═O)(C₁₋₄alkylene)NH₂,C(═O)(C₁₋₄alkylene)NH(alkyl), and/or C(═O)(C₁₋₄alkylene)N(C₁₋₄alkyl)₂.

Thus, examples of aryl groups include:

and the like, which optionally may be substituted at any availablecarbon or nitrogen atom. A preferred aryl group isoptionally-substituted phenyl.

The terms “heterocyclo” or “heterocyclic” or “cycloheteroalkyl” alone oras part of another group refers to substituted and unsubstitutednon-aromatic 3 to 7 membered monocyclic groups, 7 to 11 memberedbicyclic groups, and 10 to 15 membered tricyclic groups, in which atleast one of the rings has at least one heteroatom (O, S or N) (alsoreferred to as cycloheteroalkyl or heterocycloalkyl). Each ring of theheterocyclo group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms provided that thetotal number of heteroatoms in each ring is four or less, and furtherprovided that the ring contains at least one carbon atom. The fusedrings completing bicyclic and tricyclic groups may contain only carbonatoms and may be saturated, partially saturated, or unsaturated. Thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenatoms may optionally be quaternized. The heterocyclo group may beattached at any available nitrogen or carbon atom. The heterocyclo ringmay contain zero, one, two or three substituents selected from the groupconsisting of halogen, trifluoromethyl, trifluoromethoxy, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, nitro, cyano,oxo (═O), OR_(a), SR_(a), (═S), —NR_(a)R_(b), —N(alkyl)₃ ⁺, —NR_(a)SO₂,—NR_(a)SO₂R_(c), —SO₂R_(c) —SO₂NR_(a)R_(b), —SO₂NR_(a)C(═O)R_(b), SO₃H,—PO(OH)₂, —C(═O)R_(a), —CO₂R_(a), —C(═O)NR_(a)R_(b),—C(═O)(C₁₋₄alkylene)NR_(a)R_(b), —C(═O)NR_(a)(SO₂)R_(b),—CO₂(C₁₋₄alkylene)NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b),—NR_(a)(C₁₋₄alkylene)CO₂R_(b), ═N—OH, ═N—O-alkyl, aryl, cycloalkyl,heterocyclo, and/or heteroaryl, wherein R_(a), R_(b) and R_(c) are asdefined above for substituted alkyl groups, and are also in turnoptionally substituted as recited above. When a heterocyclo issubstituted with a further ring, said ring in turn is optionallysubstituted with one to two of (C₁₋₄alkyl, (C₂₋₄)alkenyl, halogen,hydroxy, cyano, nitro, CF₃, O(C₁₋₄alkyl), OCF₃, C(═O)H,C(═O)(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄alkyl), NHCO₂(C₁₋₄alkyl), —S(C₁₋₄alkyl),—NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, N(C₁₋₄alkyl)₃ ⁺, SO₂(C₁₋₄alkyl),C(═O)(C₁₋₄alkylene)NH₂, C(═O)(C₁₋₄alkylene)NH(alkyl), and/orC(═O)(C₁₋₄alkylene)N(C₁₋₄alkyl)₂.

Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl,imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl.

Preferred heterocyclo groups in compounds of formula (I) include

which optionally may be substituted.

The term “heteroaryl” alone or as part of another group refers tosubstituted and unsubstituted aromatic 5 or 6 membered monocyclicgroups, 9 or 10 membered bicyclic groups, and 11 to 14 memberedtricyclic groups which have at least one heteroatom (O, S or N) in atleast one of the rings. Each ring of the heteroaryl group containing aheteroatom can contain one or two oxygen or sulfur atoms and/or from oneto four nitrogen atoms provided that the total number of heteroatoms ineach ring is four or less and each ring has at least one carbon atom.The fused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. Heteroaryl groupswhich are bicyclic or tricyclic must include at least one fully aromaticring but the other fused ring or rings may be aromatic or non-aromatic.The heteroaryl group may be attached at any available nitrogen or carbonatom of any ring. The heteroaryl ring system may contain zero, one, twoor three substituents selected from the group consisting of halogen,trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, nitro, cyano, OR_(a), SR_(a), (═S),—NR_(a)R_(b), —N(alkyl)₃ ⁺, —NR_(a)SO₂, —NR_(a)SO₂R_(c), —SO₂R_(c)—SO₂NR_(a)R_(b), —SO₂NR_(a)C(═O)R_(b), SO₃H, —PO(OH)₂, —C(═O)R_(a),—CO₂R_(a), —C(═O)NR_(a)R_(b), —C(═O)(C₁₋₄alkylene)NR_(a)R_(b),—C(═O)NR_(a)(SO₂)R_(b), —CO₂(C₁₋₄alkylene)NR_(a)R_(b), oxo(═O),—NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b), —NR_(a)(C₁₋₄alkylene)CO₂R_(b), aryl,cycloalkyl, heterocyclo, and/or heteroaryl, wherein R_(a), R_(b) andR_(c) are as defined above for substituted alkyl groups, and are also inturn optionally substituted as recited above. When a heteroaryl issubstituted with a further ring, said ring in turn is optionallysubstituted with one to two of (C₁₋₄alkyl, (C₂₋₄)alkenyl, halogen,hydroxy, cyano, nitro, CF₃, O(C₁₋₄alkyl), OCF₃, C(═O)H,C(═O)(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄alkyl), NHCO₂(C₁₋₄alkyl), —S(C₁₋₄alkyl),—NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, N(C₁₋₄alkyl)₃ ⁺, SO₂(C₁₋₄alkyl),C(═O)(C₁₋₄alkylene)NH₂, C(═O)(C₁₋₄alkylene)NH(alkyl), and/orC(═O)(C₁₋₄alkylene)N(C₁₋₄alkyl)₂.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

In compounds of formula (I), preferred heteroaryl groups include

and the like, which optionally may be substituted at any availablecarbon or nitrogen atom.

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl),heterocyclo (e.g., pyrrolidinyl) or heteroaryl (e.g., imidazolyl),unless otherwise specifically indicated the reference is intended toinclude rings having 0 to 3, preferably 0-2, substituents selected fromthose recited above for the aryl, cycloalkyl, heterocyclo and/orheteroaryl groups, as appropriate.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

The term “carbocyclic” means a saturated or unsaturated monocyclic orbicyclic ring in which all atoms of all rings are carbon. Thus, the termincludes cycloalkyl and aryl rings. The carbocyclic ring may besubstituted in which case the substituents are selected from thoserecited above for cycloalkyl and aryl groups.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The term “prodrug” denotes a compound which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of the formula (I), and/or a salt and/orsolvate thereof. For example, compounds containing a carboxy group canform physiologically hydrolyzable esters which serve as prodrugs bybeing hydrolyzed in the body to yield formula (I) compounds per se. Suchprodrugs are preferably administered orally since hydrolysis in manyinstances occurs principally under the influence of the digestiveenzymes. Parenteral administration may be used where the ester per se isactive, or in those instances where hydrolysis occurs in the blood.Examples of physiologically hydrolyzable esters of compounds of formula(I) include C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl,C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Prodrug ester examples include the following groups:

(1-alkanoyloxy)alkyl such as,

wherein R^(z), R^(t) and R^(y) are H, alkyl, aryl or arylalkyl; however,R^(z)O cannot be HO.

Examples of such prodrug esters include

Other examples of suitable prodrug esters include

wherein R^(z) can be H, alkyl (such as methyl or t-butyl), arylalkyl(such as benzyl) or aryl (such as phenyl); R^(v) is H, alkyl, halogen oralkoxy, R^(u) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is 0, 1 or 2.

For further examples of prodrug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, 112:309-396, edited by K. Widder, et al.    (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and    Application of Prodrugs,” by H. Bundgaard, pp. 113-191 (1991); and-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992).

The term “tautomer” refers to compounds of the formula (I) and saltsthereof that may exist in their tautomeric form, in which hydrogen atomsare transposed to other parts of the molecules and the chemical bondsbetween the atoms of the molecules are consequently rearranged. Itshould be understood that the all tautomeric forms, insofar as they mayexist, are included within the invention.

The terms pharmaceutically acceptable “salt” and “salts” refer to basicsalts formed with inorganic and organic bases. Such salts includeammonium salts; alkali metal salts, such as lithium, sodium andpotassium salts (which are preferred); alkaline earth metal salts, suchas calcium and magnesium salts; salts with organic bases, such as aminelike salts (e.g., dicyclohexylamine salt, benzathine,N-methyl-D-glucamine, and hydrabamine salts); and salts with amino acidslike arginine, lysine and the like; and zwitterions, the so-called“inner salts”. Nontoxic, pharmaceutically acceptable salts arepreferred, although other salts are also useful, e.g., in isolating orpurifying the product.

The term pharmaceutically acceptable “salt” and “salts” also includesacid addition salts. These are formed, for example, with stronginorganic acids, such as mineral acids, for example sulfuric acid,phosphoric acid or a hydrohalic acid such as HCl or HBr, with strongorganic carboxylic acids, such as alkanecarboxylic acids of 1 to 4carbon atoms which are unsubstituted or substituted, for example, byhalogen, for example acetic acid, such as saturated or unsaturateddicarboxylic acids, for example oxalic, malonic, succinic, maleic,fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids,for example ascorbic, glycolic, lactic, malic, tartaric or citric acid,such as amino acids, (for example aspartic or glutamic acid or lysine orarginine), or benzoic acid, or with organic sulfonic acids, such as(C₁-C₄) alkyl or arylsulfonic acids which are unsubstituted orsubstituted, for example by halogen, for example methanesulfonic acid orp-toluenesulfonic acid.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

The inventive compounds may be in the free or solvate (e.g., hydrate)form.

COMBINATIONS

Where desired, the compounds of structure I may be used in combinationwith one or more other types of therapeutic agents such asimmunosuppressants, anticancer agents, anti-viral agents,anti-inflammatory agents, anti-fungal agents, antibiotics, anti-vascularhyperproliferation agents, anti-depressive agents, hypolipidemic agentsor lipid-lowering agents or lipid modulating agents, antidiabeticagents, anti-obesity agents, antihypertensive agents, plateletaggregation inhibitors, and/or anti-osteoporosis agents, which may beadministered orally in the same dosage form, in a separate oral dosageform or by injection.

The immunosuppressants which may be optionally employed in combinationwith compounds of formula I of the invention include cyclosporins, forexample cyclosporin A, mycophenolate, interferon-beta, deoxyspergolin,FK-506 or Ant.-IL-2.

The anti-cancer agents which may be optionally employed in combinationwith compounds of formula I of the invention include azathiprine,5-fluorouracil, cyclophosphamide, cisplatin, methotrexate, thiotepa,carboplatin, and the like.

The anti-viral agents which may be optionally employed in combinationwith compounds of formula I of the invention include abacavir,aciclovir, ganciclovir, zidanocin, vidarabine, and the like.

The anti-inflammatory agents which may be optionally employed incombination with compounds of formula I of the invention includenon-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, cox-2inhibitors such as celecoxib, rofecoxib, aspirin, naproxen, ketoprofen,diclofenac sodium, indomethacin, piroxicam, steroids such as prednisone,dexamethasone, hydrocortisone, triamcinolone diacetate, gold compounds,such as gold sodium thiomalate, TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRapamune) or derivatives thereof, infliximab (Remicade® Centocor, Inc.).CTLA-4Ig, LEA29Y, antibodies such as anti-ICAM-3, anti-IL-2 receptor(Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4,anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking theinteraction between CD40 and CD154 (a.k.a. “gp39”), such as antibodiesspecific for CD40 and/or CD154, fusion proteins such as etanercept,fusion proteins constructed from CD40 and/or CD154gp39 (e.g., CD40Ig andCD8gp39), inhibitors, such as nuclear translocation inhibitors, ofNF-kappa B function, such as deoxyspergualin (DSG).

The anti-fungal agents which may be optionally employed in combinationwith compounds of formula I of the invention include fluconazole,miconazole, amphotericin B, and the like.

The antibiotics which may be optionally employed in combination withcompounds of formula I of the invention include penicillin,tetracycline, amoxicillin, ampicillin, erythromycin, doxycycline,vancomycin, minocycline, clindamycin or cefalexin.

The anti-vascular hyperproliferation agents which may be optionallyemployed with compounds of formula I of the invention includemethotrexate, leflunomide, FK506 (tacrolimus, Prograf).

The hypolipidemic agent or lipid-lowering agent or lipid modulatingagents which may be optionally employed in combination with thecompounds of formula I of the invention may include 1, 2, 3 or more MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, and/or nicotinic acid and derivatives thereof.

MTP inhibitors employed herein include MTP inhibitors disclosed in U.S.Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279,U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No.5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20, 1998,now U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTPinhibitors disclosed in each of the above patents and applications.

All of the above U.S. patents and applications are incorporated hereinby reference.

Most preferred MTP inhibitors to be employed in accordance with thepresent invention include preferred MTP inhibitors as set out in U.S.Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

The hypolipidemic agent may be an HMG CoA reductase inhibitor whichincludes, but is not limited to, mevastatin and related compounds asdisclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and relatedcompounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin andrelated compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No. 0142146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al., J. Med. Chem.,31(10):1869-1871 (1988), including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design,2:1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by Ortiz deMontellano, P. et al., J. Med. Chem., 20:243-249 (1977), the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 98:1291-1293 (1976),phosphinylphosphonates reported by McClard, R. W. et al., J. Am. Chem.Soc., 109:5544 (1987), and cyclopropanes reported by Capson, T. L.,Ph.D., dissertation, Dept. Med. Chem. U. of Utah, Abstract, Table ofContents, pp. 16, 17, 40-43, 48-51, Summary (June, 1987).

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®)and cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil(HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine(SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814(azulene derivative), melinamide (Sumitomo), Sandoz 58-035, AmericanCyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives),nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylicacid, aspirin, poly(diallylmethylamine) derivatives such as disclosed inU.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The hypolipidemic agent may be an ACAT inhibitor such as disclosed in,Drugs of the Future, 24:9-15 (1999) (Avasimibe); Nicolosi et al., “TheACAT inhibitor, C1-1011 is effective in the prevention and regression ofaortic fatty streak area in hamsters”, Atherosclerosis (Shannon, Irel.),137(1):77-85 (1998); Ghiselli, G., “The pharmacological profile of FCE27677: a novel ACAT inhibitor with potent hypolipidemic activitymediated by selective suppression of the hepatic secretion ofApoB100-containing lipoprotein”, Cardiovasc. Drug Rev., 16(1):16-30(1998); Smith, C. et al., “RP 73163: a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor”, Bioorg. Med. Chem.Lett., 6(1):47-50 (1996); Krause et al., “ACAT inhibitors: physiologicmechanisms for hypolipidemic and anti-atherosclerotic activities inexperimental animals”, Inflammation: Mediators Pathways, Publisher: CRC,Boca Raton, Fla., Editor(s): Ruffolo, Robert R., Jr., Hollinger,Mannfred A., pp. 173-198 (1995); Sliskovic et al., “ACAT inhibitors:potential anti-atherosclerotic agents”, Curr. Med. Chem., 1(3):204-225(1994); Stout et al., “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”, Chemtracts: Org. Chem.,8(6):359-e62 (1995), or TS-962 (acetamide,N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-) (TaishoPharmaceutical Co. Ltd.).

The hypolipidemic agent may be an upregulator of LD2 receptor activitysuch as MD-700 (1(3H)-isobenzofuranone,3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy) (Taisho PharmaceuticalCo. Ltd) and LY295427 (cholestan -3-ol, 4-(2-propenyl)-, (3a, 4a, 5a)-)(Eli Lilly).

The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's ezetimibe (SCH58235) and SCH48461 as wellas those disclosed in Atherosclerosis, 115:45-63 (1995) and J. Med.Chem., 41:973 (1998).

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24:425-430 (1999).

The lipid-modulating agent may be a cholesteryl ester transfer protein(CETP) inhibitor such as Pfizer's CP 529,414 (torcetrapib) (WO/0038722and EP 818448) and Pharmacia's SC-744 and SC-795.

The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, itavastatin and visastatin andZD-4522.

The above-mentioned U.S. patents are incorporated herein by reference.The amounts and dosages employed will be as indicated in the Physicians'Desk Reference and/or in the patents set out above.

The compounds of formula I of the invention will be employed in a weightratio to the hypolipidemic agent (were present), within the range fromabout 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The dosages and formulations for the hypolipidemic agent will be asdisclosed in the various patents and applications discussed above.

The dosages and formulations for the other hypolipidemic agent to beemployed, where applicable, will be as set out in the latest edition ofthe Physicians' Desk Reference.

For oral administration, a satisfactory result may be obtained employingthe MTP inhibitor in an amount within the range of from about 0.01 mg toabout 500 mg and preferably from about 0.1 mg to about 100 mg, one tofour times daily.

A preferred oral dosage form, such as tablets or capsules, will containthe

MTP inhibitor in an amount of from about 1 to about 500 mg, preferablyfrom about 2 to about 400 mg, and more preferably from about 5 to about250 mg, one to four times daily.

For oral administration, a satisfactory result may be obtained employingan HMG CoA reductase inhibitor, for example, pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin or cerivastatin in dosagesemployed as indicated in the Physicians' Desk Reference, such as in anamount within the range of from about 1 to 2000 mg, and preferably fromabout 4 to about 200 mg.

The squalene synthetase inhibitor may be employed in dosages in anamount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will containthe HMG CoA reductase inhibitor in an amount from about 0.1 to about 100mg, preferably from about 0.5 to about 80 mg, and more preferably fromabout 1 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will containthe squalene synthetase inhibitor in an amount of from about 10 to about500 mg, preferably from about 25 to about 200 mg.

The hypolipidemic agent may also be a lipoxygenase inhibitor including a15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives asdisclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613,isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors asdisclosed by Sendobry et al., “Attenuation of diet-inducedatherosclerosis in rabbits with a highly selective 15-lipoxygenaseinhibitor lacking significant antioxidant properties”, Brit. J.Pharmacology, 120:1199-1206 (1997), and Cornicelli et al.,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 5:11-20 (1999).

The compounds of formula I and the hypolipidemic agent may be employedtogether in the same oral dosage form or in separate oral dosage formstaken at the same time.

The compositions described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin as well as niacinand/or cholestagel.

The other antidiabetic agent which may be optionally employed incombination with the compound of formula I may be 1, 2, 3 or moreantidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, or other antidiabetic agentspreferably having a mechanism of action different from the compounds offormula I of the invention, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPAR γ agonists, such asthiazolidinediones, aP2 inhibitors, dipeptidyl peptidase IV (DP4)inhibitors, SGLT2 inhibitors, and/or meglitinides, as well as insulin,and/or glucagon-like peptide-1 (GLP-1).

The other antidiabetic agent may be an oral antihyperglycemic agentpreferably a biguanide such as metformin or phenformin or salts thereof,preferably metformin HCl.

Where the antidiabetic agent is a biguanide, the compounds of structureI will be employed in a weight ratio to biguanide within the range fromabout 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.

The other antidiabetic agent may also preferably be a sulfonyl urea suchas glyburide (also known as glibenclamide), glimepiride (disclosed inU.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the β-cells, with glyburide and glipizide beingpreferred, which may be administered in the same or in separate oraldosage forms.

The compounds of structure I will be employed in a weight ratio to thesulfonyl urea in the range from about 0.01:1 to about 100:1, preferablyfrom about 0.02:1 to about 5:1.

The oral antidiabetic agent may also be a glucosidase inhibitor such asacarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosedin U.S. Pat. No. 4,639,436), which may be administered in the same or ina separate oral dosage forms.

The compounds of structure I will be employed in a weight ratio to theglucosidase inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.05:1 to about 10:1.

The compounds of structure I may be employed in combination with a PPARγ agonist such as a thiazolidinedione oral anti-diabetic agent or otherinsulin sensitizers (which has an insulin sensitivity effect in NIDDMpatients) such as troglitazone (Warner-Lambert's Rezulin®, disclosed inU.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda),Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Wellcome's GL-262570 (farglitazar), englitazone (CP-68722, Pfizer)or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(reglitazar) (JPNT/P&U), L-895645 (Merck), R-119702 (rivoglitazone)(Sankyo/WL), NN-2344 (balaglitazone) (Dr. Reddy/NN), or YM-440((Z)-1,4-bis-4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl-methyl)]phenoxybut-2-ene)(Yamanouchi), preferably rosiglitazone and pioglitazone.

The compounds of structure I will be employed in a weight ratio to thethiazolidinedione in an amount within the range from about 0.01:1 toabout 100:1, preferably from about 0.05 to about 10:1.

The sulfonyl urea and thiazolidinedione in amounts of less than about150 mg oral antidiabetic agent may be incorporated in a single tabletwith the compounds of structure I.

The compounds of structure I may also be employed in combination with aantihyperglycemic agent such as insulin or with glucagon-like peptide-1(GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (asdisclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of whichis incorporated herein by reference), as well as AC2993 (exenatide)(Amylin) and LY-315902 (8-37-glucagon-like peptide I (human),N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine]-)(Lilly), which may be administered via injection, intranasal, inhalationor by transdermal or buccal devices.

Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physicians' DeskReference (PDR).

Where present, metformin or salt thereof may be employed in amountswithin the range from about 500 to about 2000 mg per day which may beadministered in single or divided doses one to four times daily.

Where present, the thiazolidinedione anti-diabetic agent may be employedin amounts within the range from about 0.01 to about 2000 mg/day whichmay be administered in single or divided doses one to four times perday.

Where present insulin may be employed in formulations, amounts anddosing as indicated by the Physicians' Desk Reference.

Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. No. 5,346,701 (TheraTech), U.S. Pat. No. 5,614,492 and U.S.Pat. No. 5,631,224 which are incorporated herein by reference.

The other antidiabetic agent may also be a PPAR α/γ dual agonist such asAR-HO39242 (tesaglitazar) (Astra/Zeneca), GW-409544 (Glaxo-Wellcome),KRP297 (benzamide,5-[(2,4-dioxo-5-thiazolidinyl)methy1]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-(KyorinMerck) as well as those disclosed by Murakami et al., “A Novel InsulinSensitizer Acts As a Coligand for Peroxisome Proliferation-ActivatedReceptor Alpha (PPAR alpha) and PPAR gamma Effect on PPAR alphaActivation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats”,Diabetes, 47:1841-1847 (1998).

The antidiabetic agent may be an SGLT2 inhibitor such as disclosed inU.S. application Ser. No. 09/679,027, filed Oct. 4, 2000, employingdosages as set out therein. Preferred are the compounds designated aspreferred in the above application.

The antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S.application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.application Ser. No. 09/519,079, filed Mar. 6, 2000, employing dosagesas set out herein. Preferred are the compounds designated as preferredin the above application.

The antidiabetic agent may be a DP4 inhibitor such as disclosed in U.S.application Ser. No. 09/788,173 filed Feb. 16, 2001, WO99/38501,WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431(PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al., Biochemistry,38(36):11597-11603 (1999), TSL-225(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett., 8:1537-1540 (1998),2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal., Bioorg. & Med. Chem. Lett., 6(22):1163-1166 and 2745-2748 (1996)employing dosages as set out in the above references.

The meglitinide which may optionally be employed in combination with thecompound of formula I of the invention may be repaglinide, nateglinide(Novartis) or KAD1229 (mitiglinide) (PF/Kissei), with repaglinide beingpreferred.

The compound of formula I will be employed in a weight ratio to themeglitinide, PPAR γ agonist, PPAR α/γ dual agonist, aP2 inhibitor, DP4inhibitor or SGLT2 inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.05 to about 10:1.

The other type of therapeutic agent which may be optionally employedwith a compound of formula I may be 1, 2, 3 or more of an anti-obesityagent including a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin (and dopamine) reuptake inhibitor, an aP2 inhibitor, a thyroidreceptor agonist and/or an anorectic agent.

The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677 (rafabegron)(Takeda/Dainippon), L750355 (benzenesulfonamide,N-[4-[2-[[(25)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-)(Merck), or CP331684(4-[2-[[2-(6-aminopyridin-3-yl)-2(R)-hydroxyethyl]-amino]ethoxy]phenyl]aceticacid) (Pfizer) or other known beta 3 agonists as disclosed in U.S. Pat.Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, withAJ9677, L750,355 (benzenesulfonamide,N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-)and CP331684 being preferred.

The lipase inhibitor which may be optionally employed in combinationwith a compound of formula I may be orlistat or ATL-962 (Alizyme), withorlistat being preferred.

The serotonin (and dopamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of formula I may be sibutramine,topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramineand topiramate being preferred.

The thyroid receptor agonist which may be optionally employed incombination with a compound of formula I may be a thyroid receptorligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio),WO00/039077 (KaroBio), and U.S. Provisional Application 60/183,223 filedFeb. 17, 2000, with compounds of the KaroBio applications and the aboveU.S. provisional application being preferred.

The anorectic agent which may be optionally employed in combination witha compound of formula I may be dexamphetamine, phentermine,phenylpropanolamine or mazindol, with dexamphetamine being preferred.

The various anti-obesity agents described above may be employed in thesame dosage form with the compound of formula I or in different dosageforms, in dosages and regimens as generally known in the art or in thePDR.

The antihypertensive agents which may be employed in combination withthe compound of formula I of the invention include ACE inhibitors,angiotensin II receptor antagonists, NEP/ACE inhibitors, as well ascalcium channel blockers, β-adrenergic blockers and other types ofantihypertensive agents including diuretics.

The angiotensin converting enzyme inhibitor which may be employed hereinincludes those containing a mercapto (—S—) moiety such as substitutedproline derivatives, such as any of those disclosed in U.S. Pat. No.4,046,889 to Ondetti et al mentioned above, with captopril, that is,1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, andmercaptoacyl derivatives of substituted prolines such as any of thosedisclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.

Other examples of mercapto containing ACE inhibitors that may beemployed herein include rentiapril (fentiapril, Santen) disclosed inClin. Exp. Pharmacol. Physiol., 10:131 (1983); as well as pivopril andYS980.

Other examples of angiotensin converting enzyme inhibitors which may beemployed herein include any of those disclosed in U.S. Pat. No.4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred, any of the phosphonate substituted amino orimino acids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolineor (ceronapril) being preferred, phosphinylalkanoyl prolines disclosedin U.S. Pat. No. 4,168,267 mentioned above with fosinopril beingpreferred, any of the phosphinylalkanoyl substituted prolines disclosedin U.S. Pat. No. 4,337,201, and the phosphonamidates disclosed in U.S.Pat. No. 4,432,971 discussed above.

Other examples of ACE inhibitors that may be employed herein includeBeecham's BRL 36,378 as disclosed in European Patent Application Nos.80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v and Jap.J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res., 39:671 (1986); 40:543 (1986);ramipril (Hoechst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.Res., 40:74 (1986); Ru 44570 (Hoechst) disclosed inArzneimittelforschung, 34:1254 (1985), cilazapril (Hoffman-LaRoche)disclosed in J. Cardiovasc. Pharmacol.,9:39 (1987); R 31-2201(Hoffman-LaRoche) disclosed in FEBS Lett., 165:201 (1984); lisinopril(Merck), indalapril (delapril) disclosed in U.S. Pat. No. 4,385,051;indolapril (Schering) disclosed in J. Cardiovasc. Pharmacol., 5:643, 655(1983), spirapril (Schering) disclosed in Acta. Pharmacol. Toxicol.,59(Supp. 5):173 (1986); perindopril (Servier) disclosed in Eur. J. Clin.Pharmacol., 31:519 (1987); quinapril (Warner-Lambert) disclosed in U.S.Pat. No. 4,344,949 and CI925 (Warner-Lambert)([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl) disclosed in Pharmacologist, 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem., 26:394 (1983).

Preferred ACE inhibitors are captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

NEP/ACE inhibitors may also be employed herein in that they possessneutral endopeptidase (NEP) inhibitory activity and angiotensinconverting enzyme (ACE) inhibitory activity. Examples of NEP/ACEinhibitors suitable for use herein include those disclosed in U.S. Pat.Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688,U.S. Pat. No. 5,552,397, U.S. Pat. No. 5,504,080, U.S. Pat. No.5,612,359,U.S. Pat. No. 5,525,723, European Patent Application 0599444,0481522, 0599444, 0595610, European Patent Application 0534363A2, 534396and 534492, and European Patent Application 0629627A2.

Preferred are those NEP/ACE inhibitors and dosages thereof which aredesignated as preferred in the above patents/applications which U.S.patents are incorporated herein by reference; most preferred areomapatrilat([S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat)) and CGS 30440.

The angiotensin II receptor antagonist (also referred to herein asangiotensin II antagonist or All antagonist) suitable for use hereinincludes, but is not limited to, irbesartan, losartan, valsartan,candesartan, telmisartan, tasosartan or eprosartan, with irbesartan,losartan or valsartan being preferred.

A preferred oral dosage form, such as tablets or capsules, will containthe ACE inhibitor or AII antagonist in an amount within the range fromabut 0.1 to about 500 mg, preferably from about 5 to about 200 mg andmore preferably from about 10 to about 150 mg.

For parenteral administration, the ACE inhibitor, angiotensin IIantagonist or NEP/ACE inhibitor will be employed in an amount within therange from about 0.005 mg/kg to about 10 mg/kg and preferably from about0.01 mg/kg to about 1 mg/kg.

Where a drug is to be administered intravenously, it will be formulatedin conventional vehicles, such as distilled water, saline, Ringer'ssolution or other conventional carriers.

It will be appreciated that preferred dosages of ACE inhibitor and AIIantagonist as well as other antihypertensives disclosed herein will beas set out in the latest edition of the Physicians' Desk Reference(PDR).

Other examples of preferred antihypertensive agents suitable for useherein include omapatrilat (Vanlev®) amlodipine besylate (Norvasc®),prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem,felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol,sotalol, terazosin, doxazosin, propranolol, and clonidine HCl(Catapres®).

Diuretics which may be employed in combination with compounds of formulaI include hydrochlorothiazide, torasemide, furosemide, spironolactono,and indapamide.

Antiplatelet agents which may be employed in combination with compoundsof formula I of the invention include aspirin, clopidogrel, ticlopidine,dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide, andifetroban, with clopidogrel and aspirin being preferred.

The antiplatelet drugs may be employed in amounts as indicated in thePDR. Ifetroban may be employed in amounts as set out in U.S. Pat. No.5,100,889.

Antiosteoporosis agents suitable for use herein in combination with thecompounds of formula I of the invention include parathyroid hormone orbisphosphonates, such as MK-217 (alendronate) (Fosamax®).

Dosages employed for the above drugs will be as set out in thePhysicians' Desk Reference.

PHARMACEUTICAL FORMULATIONS

The pharmaceutical composition of the invention includes apharmaceutically acceptable carrier, adjuvant or vehicle that may beadministered to a subject, together with a compound of the presentinvention, and which does not destroy the pharmacological activitythereof. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of the presentinvention include, but are not limited to, the following: ionexchangers, alumina, aluminum stearate, lecithin, self-emulsifying drugdelivery systems (“SEDDS”) such as d(-tocopherol polyethyleneglycol 1000succinate), surfactants used in pharmaceutical dosage forms such asTweens or other similar polymeric delivery matrices, serum proteins suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β- and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be used to enhance delivery of the modulators of the presentinvention.

The compositions of the present invention may contain other therapeuticagents as described below, and may be formulated, for example, byemploying conventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

The compounds of the invention may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; buccally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents. Thecompounds of the invention may, for example, be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved by the use of suitable pharmaceuticalcompositions including the compounds of the invention, or, particularlyin the case of extended release, by the use of devices such assubcutaneous implants or osmotic pumps. The compounds of the inventionmay also be administered liposomally.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The present compounds may also be delivered through the oralcavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating thecompound(s) of the invention with fast dissolving diluents such asmannitol, lactose, sucrose and/or cyclodextrins. Also included in suchformulations may be high molecular weight excipients such as celluloses(Avicel) or polyethylene glycols (PEG). Such formulations may alsoinclude an excipient to aid mucosal adhesion such as hydroxy propylcellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), andagents to control release such as polyacrylic copolymer (e.g., Carbopol934). Lubricants, glidants, flavors, coloring agents and stabilizers mayalso be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquefy and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.1 to 500 mg/kg of bodyweight of active compound per day, or between 5 and 2000 mg per daywhich may be administered in a single dose or in the form of individualdivided doses, such as from 1 to 5 times per day. It will be understoodthat the specific dose level and frequency of dosage for any particularsubject may be varied and will depend upon a variety of factorsincluding the activity of the specific compound employed, the metabolicstability and length of action of that compound, the species, age, bodyweight, general health, sex and diet of the subject, the mode and timeof administration, rate of excretion, drug combination, and severity ofthe particular condition. Preferred subjects for treatment includeanimals, most preferably mammalian species such as humans, and domesticanimals such as dogs, cats and the like.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

The compounds of the examples are inhibitors of AP-1 activity and/orcompete with known ligands of the glucocorticoid receptor.

Compounds of the invention, including the compounds described in theexamples, have been tested in at least one of the assays described belowand have glucocorticoid receptor (GR)/Dexamethasone (Dex) inhibitoryactivity and/or AP-1 inhibitory activity.

ASSAYS GR Binding Assays Glucocorticoid Receptor Binding Assay (I)

In order to assess the affinity of test compounds for the humanglucocorticoid receptor, a commercially available kit was used(Glucocorticoid Receptor Competitor Assay Kit, Invitrogen Part #2893).Briefly, purified human recombinant full-length glucocorticoid receptor(2 nM) was mixed with fluorescently labeled glucocorticoid (1 nMFluormone GS Red) in the presence or absence of test compound. After twohour incubation at room temperature in the dark, the fluorescencepolarization (FP) of the samples was measured. The FP of a mixture ofreceptor, fluorescent probe (i.e. Fluormone GS Red) and 5 μMdexamethasone represented background fluorescence or 100% inhibition,whereas, the FP of the mixture without dexamethasone (but in thepresence of vehicle) was taken to be 100% binding. The percentageinhibition of test compounds were then compared to the sample with 5 μMdexamethasone and expressed as % relative binding activity withdexamethasone being 100% and no inhibition being 0%. Test compounds wereanalyzed in the concentration range from 8.5E-05 μM to 5 μM.

Glucocorticoid Receptor Binding Assay (II)

In order to measure the binding of compounds on the glucocorticoidreceptor a commercially available kit was used (Glucocorticoid receptorcompetitor assay kit, PanVera Co., Madison, Wis., P2816). Briefly, acell lysate containing recombinantly expressed human full-lengthglucocorticoid receptor was mixed with a fluorescently labeledglucocorticoid (1 nM Fluormone GS1) in the presence or absence of testcompound. After one hour at room temperature, the fluorescencepolarization (FP) of the samples were measured. The FP of a mixture ofreceptor, fluorescent probe (i.e. Fluormone GS1) and 1 mM dexamethasonerepresented background fluorescence or 100% inhibition, whereas, the FPof the mixture without dexamethasone was taken to be 100% binding. Thepercentage inhibition of test molecules were then compared to the samplewith 1 mM dexamethasone and expressed as % relative binding activitywith dexamethasone being 100% and no inhibition being 0%. Test moleculeswere analyzed in the concentration range from 2.4 nM to 40 microMolar.

Cellular Transrepressional Assay

To measure the ability of test molecules to inhibit AP-1 inducedtranscriptional activity an A549 cell was utilized which was stablytransfected with a plasmid containing 7× AP-1 DNA binding sites(pAP-1-Luc plasmid, Stratagene Co. La Jolla, Calif.) followed by thegene for luciferase. Cells were activated with 10 ng/ml of phorbolmyristic acid (PMA) plus or minus test molecules for 7 hours. After 7hours a luciferase reagent was added to measure luciferase enzymaticactivity in the cell. After a 10 minute incubation of luciferase reagentwith cells, luminescence was measured in a TopCount luminescencecounter. Repression of AP-1 activity was calculated as the percentagedecrease in the signal induced by PMA alone. Test molecules wereanalyzed in the concentration range from 0.1 nM to 40 μM. EC50s weredetermined by using standard curve fitting methods such as Excel fit(Microsoft Co.). An EC50 is the test molecule concentration at whichthere is a 50% repression of the maximal inhibition of transcription,i.e. a 50% reduction of AP-1 activity. In the absence of an EC50 themaximum % inhibition recorded is the inhibition of AP-1 at a compoundconcentration of 10 micromolar.

Other reporters and cell lines also may be used in a cellulartransrepressional assay. A similar assay is performed in which NF-κBactivity is measured. A plasmid containing NF-κB DNA binding sites isused, such as pNF-kB-Luc, (Stratagene, LaJolla Calif.), and PMA oranother stimulus, such as TNF-α or lipopolysaccharide, is used toactivate the NF-κB pathway. NF-κB assays similar to that described inYamamoto K. et al., J. Biol. Chem., 270(52):31315-31320 (Dec. 29, 1995)may be used.

The cellular transrepressional assays described above may be used tomeasure transrepression by any NHR. One of skill in the art willunderstand that assays may require the addition of components, such as astimulus (e.g., PMA, lipopolysaccharide, TNF-α, etc.) which will inducetranscription mediated by AP-1 or NF-κB.

Additionally, AR mediated transrepression may be measured by the assaydescribed in Palvimo. J. J. et al., J. Biol. Chem., 271(39):24151-24156(Sep. 27, 1996), and PR mediated transrepression may be measured by theassay described in Kalkhoven E. et al., J. Biol. Chem.,271(11):6217-6224 (Mar. 15, 1996).

ABBREVIATIONS

The following abbreviations are employed in the following Preparationsand Examples:

-   Ph=phenyl-   Bn=benzyl-   t-Bu=tertiary butyl-   Me=methyl-   Et=ethyl-   ACN=acetonitrile-   TMS=trimethylsilyl-   TMSN₃=trimethylsilyl azide-   TBS=tert-butyldimethylsilyl-   FMOC=fluorenylmethoxycarbonyl-   Boc=tert-butoxycarbonyl-   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   THF=tetrahydrofuran-   Et₂O=diethyl ether-   hex=hexanes-   EtOAc=ethyl acetate-   DMF=dimethyl formamide-   MeOH=methanol-   EtOH=ethanol-   i-PrOH=isopropanol-   DMSO=dimethyl sulfoxide-   DME=1,2 dimethoxyethane-   DCE=1,2 dichloroethane-   HMPA=hexamethyl phosphoric triamide-   HOAc or AcOH=acetic acid-   TFA=trifluoroacetic acid-   TFAA=trifluoroacetic anhydride-   i-Pr₂NEt=diisopropylethylamine-   Et₃N=triethylamine-   NMM=N-methyl morpholine-   DMAP=4-dimethylaminopyridine-   NaBH₄=sodium borohydride-   NaBH(OAc)₃=sodium triacetoxyborohydride-   DIBALH=diisobutyl aluminum hydride-   LAH or LiAlH₄=lithium aluminum hydride-   n-BuLi=n-butyllithium-   LDA=lithium diisopropylamide-   Pd/C=palladium on carbon-   PtO₂=platinum oxide-   KOH=potassium hydroxide-   NaOH=sodium hydroxide-   LiOH=lithium hydroxide-   K₂CO₃=potassium carbonate-   NaHCO₃=sodium bicarbonate-   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene-   EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or    EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or    1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)-   HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate-   HOAT=1-Hydroxy-7-azabenzotriazole-   BOP reagent=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium    hexafluorophosphate-   NaN(TMS)₂=sodium hexamethyldisilazide or sodium    bis(trimethylsilyl)amide-   Ph₃P=triphenylphosphine-   Pd(OAc)₂=Palladium acetate-   (Ph₃P)₄Pd^(o)=tetrakis triphenylphosphine palladium-   DEAD=diethyl azodicarboxylate-   DIAD=diisopropyl azodicarboxylate-   Cbz-Cl=benzyl chloroformate-   CAN=ceric ammonium nitrate-   SAX=Strong Anion Exchanger-   SCX=Strong Cation Exchanger-   Ar=argon-   N₂=nitrogen-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   meq=milliequivalent-   rt or RT=room temperature-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   Reverse phase HPLC=reverse phase high performance liquid    chromatography, using a YMC ODS S5 column and a binary solvent    A/solvent B eluents-   Solvent A=10% MeOH—90% H₂O—0.1% TFA-   Solvent B=90% MeOH—10% H₂O—0.1% TFA; or-   Solvent A=H₂O containing 0.1% TFA-   Solvent B=ACN containing 0.1% TFA-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NMR=nuclear magnetic resonance-   NMR spectral data: s=singlet; d=doublet; m=multiplet; br=broad;    t=triplet mp=melting point

EXAMPLES

The following Examples illustrate embodiments of the inventive compoundsand starting materials, and are not intended to limit the scope of theclaims.

Preparations

The preparations set out below are for the synthesis of reagents thatwere not obtained from commercial sources and were employed for thepreparation of compounds of formula I of the invention. All chiralcompounds in the tables and schemes are racemic unless specifiedotherwise.

Reverse-phase preparative high performance liquid chromatography(“HPLC”) was performed with Shimadzu 8A liquid chromatographs using YMCS5 ODS columns (20×100, 20×250, or 30×250 millimeter (“mm”)). Gradientelution was performed with methanol (“MeOH”)/water mixtures in thepresence of 0.1% trifluoroacetic acid (“TFA”).

Analytical HPLC Method Employed in Characterization of Examples

Analytical HPLC was performed on Shimadzu LC10AS liquid chromatographsusing the following methods:

Method A (Used in All Cases, Unless Otherwise Indicated):

-   Linear gradient of 0 to 100% solvent B over 4 minutes (“min”), with    1 minute (“min”) hold at 100% B.-   Ultraviolet (“UV”) visualization at 220 nanometers (“nm”)-   Column: YMC S5 ODS Ballistic 4.6×50 mm-   Flow rate: 4 milliliters (“mL”)/min-   Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol-   Solvent B: 0.2% phosphoric acid, 90% methanol, 10% water

Method B:

Column: Phenomenex Luna C18(2), 4.6 × 50 mm × 5 um (A) 10:90methanol:water; (B) 90:10 Mobile Phase: methanol:water Buffer: 0.1% TFAGradient Range: 0-100% B Gradient Time: 4 min Flow Rate: 4 mL/minAnalysis Time: 5 min Detection: Detector 1: UV at 220 nm Detector 2: MS(ESI+) Detector 3: ELSD

Purification of Final Compounds of Formula I

All of the examples that are described below that contain one or morechiral centers can be resolved using standard or chiral HPLCchromatography. Purification of diastereomers or regioisomers wasperformed using HPLC (Phenomenex Luna column: 3×25 cm 5 mM C18; solvent:water (containing 0.5% TFA) with increasing acetonitrile (containing0.5% TFA) gradients over 25 min; flow rate: 40 mL/min; uv detection at215 nM). Another HPLC method makes use of a YMC S5 CombiScreen column:4.6×50 mm C18; solvent: 10-90% aqueous methanol over 4 minutescontaining 0.2% phosphoric acid; flow rate: 4 mL/min; uv detection at220 nM

Chiral separation of enantiomers was performed using preparativeChiracel AD, OJ, or AS columns and isocratic mobile phases of EtOH orMeOH mixed with heptane. Alternatively, the same Chiracel columns couldbe run using SFC methods with mobile phases such as CO₂, MeOH, anddiethylamine. Note that enantiomers may be separated after the finalstage of synthesis or earlier at any intermediate chiral precursor inthe synthetic route and then taken to the end of the synthetic sequenceenantiomerically pure.

General Coupling Method A:

To a solution of carboxylic acid (0.15 mmol) in DMF (1-2 mL) was addedhydroxybenzotriazole (31 mg, 0.23 mmol), triethylamine (0.3 mmol), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (43 mg, 0.23 mmol). Afterstirring for 10 min, the Z—Z_(a)—NH₂ amine (0.23 mmol) was added and thereaction is heated between 80-100 C for 3-24 h. The reaction was cooledand the reaction purified by HPLC. Products were identified by MS andconsistent ¹H-NMR spectra.

General Coupling Method B:

To a solution of carboxylic acid (e.g.,3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoicacid) (16 mmol) and pyridine (1.5 mL, 18.5 mmol) in 300 mL of CH₂Cl₂ wasadded cyanuric fluoride (1.6 mL, 18.8 mmol). The reaction was stirredfor 1 hr, then quenched with 1N HCl and extracted with 2×CH₂Cl₂. TheCH₂Cl₂ extracts were dried over MgSO₄, filtered, and concentrated byrotary evaporator to give the corresponding crude acid fluoride. Thisintermediate was characterized using MS and ¹H-NMR. The crude acidfluoride was combined with the Z—Z_(a)—NH₂ amine in a suitable solvent(DCM, THF, DMF) without base and heated to 85° C. for 16 hr. Forhindered acids, the acid fluoride (0.06 mmol), the Z—Z_(a)—NH₂ amine(0.12 mmol), and DMAP (0.03 mmol) are dissolved in dry NMP and reactedin a microwave at 150° C. for approximately 30 min. The final productswere purified using HPLC and the final products were identified by MSand consistent ¹H-NMR spectra.

Example 13-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide

The procedure of Scheme A was used in preparing the Example 1 compound.

-   (a) Following the general procedure of Sun et al. (J. Org. Chem.,    62:5627-5629 (1997)), 4-amino-3-methyl-benzyl alcohol (36.8 g, 269    mmol) was dissolved in dry chloroform (1 L) followed by potassium    acetate (53 g, 540 mmol), and acetic anhydride (83 g, 810 mmol).    After 2 h, the reaction was refluxed for 3 h and then cooled to rt    and stirred overnight.-   (b) The next day, 18-crown-6 ether (3.6 g, 13.5 mmol) was added    followed by isoamyl nitrite (71.3 g, 608 mmol). The reaction was    refluxed for 20 h, cooled to rt, washed with sat NaHCO₃, and the    organic layer was dried over MgSO₄, filtered, and concentrated in    vacuo. The crude oil was passed through a SiO₂ plug first with 5%    EtOAc in hexanes, then 20% EtOAc in hexanes and concentrated. The    residue was triturated with Et₂O/hexane to obtain 23.3 g of solid,    bis-acetylated product. The supernatant was concentrated and the    titration procedure repeated twice to give an additional 12.2 g.    Total yield: 35.5 g (57% yield). MS found: (M+H)⁺=233.-   (c) The solid was dissolved in MeOH (350 mL) and treated with 1 M    NaOH (150 mL). After stirring overnight, the MeOH was removed in    vacuo, the residue acidified with conc HCl to pH 4-5 and extracted    with EtOAc×3. The organic layer was dried with MgSO₄, filtered,    concentrated in vacuo to give 20.1 g (90%) of    (1H-indazol-5-yl)methanol. MS found: (M+H)⁺=149.-   (d) (1H-Indazol-5yl)methanol (2.7 g, 18.2 mmol) was dissolved in 20    mL dry dioxane in a stainless steel pressure tube.    Trans-1,2-cyclohexanediamine (1.1 mL, 9.12 mmol) was added followed    by CuI (174 mg, 0.91 mmol) and then K₃PO₄ (6.97 g, 32.8 mmol). After    the addition of 4-fluoro-1-iodobenzene (2.1 mL, 18.2 mmol), the    reactor was sealed and heated at 100 C for 24 h. The reactor was    cooled and the contents were taken up in EtOAc, filtered through a    SiO₂ plug with EtOAc and concentrated in vacuo. The crude product    was chromatographed using 31:1 EtOAc/hexanes to give 4.25 g (96%    yield) of a pale yellow oil    (1-(4-fluorophenyl)-1H-indazol-5-yl)methanol that solidified on    standing. MS found: (M+H)⁺=243.-   (e) (1-(4-Fluorophenyl)-1H-indazol-5-yl)methanol (2.46 g, 10.2 mmol)    was dissolved in 80 mL DCM and treated with commercially available    Dess-Martin periodinane (4.3 g, 10.2 mmol). The reaction was    complete in 2 h and was filtered through a plug of SiO₂ using    DCM/hexane (3:1) and concentrated to give 2.47 g (100%) of    1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde. MS found:    (M+H)⁺=241.-   (f) 1-(4-Fluorophenyl)-1H-indazol-5-carboxaldehyde (2.47 g, 10 2    mmol) was dissolved in 25 mL THF, cooled in a 0° C. ice bath, and    treated with PhMgBr (4.6 mL of 1.0 M in THF, 4.58 mmol). After 1 h,    the reaction was quenched with sat. NH₄Cl and extracted with    EtOAc×3. The organic layers were dried over MgSO₄, filtered, and    concentrated to give 3.2 g (100%) of product    (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol. MS found:    (M+H)⁺=319.-   (g) (1-(4-Fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (16.0 g, 50    mmol) was dissolved in 400 mL of dry THF and TiCl₄ (60 mL of 1.0 M    DCM solution, 60 mmol) was added portionwise and then stirred 30    min. The flask was put on a rotary evaporator until the THF began to    distill to degas the HCl and then the reaction was treated with    1-methoxy-2-methyl-1-(trimethylsiloxy)propene (17.4 g, 100 mmol).    The reaction was quenched with aqueous sodium bicarbonate and    extracted 2×EtOAc, the organic layers dried over MgSO₄, filtered,    concentrated, and then chromatographed using DCM to give 16.2 g (81%    yield) of methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate.    MS found: (M+H)⁺=403.-   (h) Methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate    (16.2 g, 40.2 mmol) was heated to 100 C overnight in a mixture of 2    M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled,    acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers    were washed with water×2, dried over MgSO₄, filtered, and    concentrated in vacuo to give 15.4 g (99% yield) of acid    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic    acid. MS found: (M+H)⁺=389.-   (i) Example 1 was prepared from    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic    acid (100 mg, 0.26 mmol) and 2-aminothiazole using General Coupling    Method A to give 52 mg (42% yield). MS found: (M+H)⁺=471. 400 MHz    ¹H-NMR (DMSO-d6) δ 12.0 (s, 1H); 8.36 (s, 1H); 7.93 (s, 1H); 7.77    (dd, 2H); 7.70 (d, 1H); 7.46 (dd, 2H); 7.40 (m, 4H); 7.28 (app t,    2H); 7.20 (app t, 1H); 7.16 (d, 1H); 5.10 (s, 1H); 1.36 (s, 6H)    Resolution of this compound into its enantiomers could be    accomplished using chiral HPLC as described above.

Examples 2 to 28

Following a procedure similar to that set out in Scheme A and Example 1,the following compounds were obtained.

(M + H)+/ se- Coup- lec- ling ted Meth- Ex. Name Product Structure AmineNMR od 2 3-(1-(4-fluoro-phenyl)-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4- thiadiazol-2- yl)propanamide

(M − H)⁻ 470 A 400 MHz ¹H-NMR (DMSO-d6) δ 12.5 (s, 1 H); 9.09 (s, 1 H);8.36 (s, 1 H); 7.92 (s, 1 H); 7.77 (dd, 2 H); 7.68 (d, 1 H); 7.41 (m, 5H); 7.27 (app t, 2 H); 7.19 (app t, 1 H); 5.07 (s, 1 H); 1.36 (s, 6 H).3 N-cyclopentyl-3-(1-(4- fluorophenyl)-1H-indazol- 5-yl)-2,2-dimethyl-3-phenylpropanamide

456 A 4 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-N-(1-methyl-1H-pyrazol-3- yl)-3-phenylpropanamide

468 B NMR (CDCl₃) δ 8.05 (s, 1 H); 7.76 (s, 1 H) 7.5-7.6 (m, 2 H);7.4-7.45 (d, 1 H); 7.28-7.4 (m, 4 H); 7.1-7.26 (m, 5 H); 6.70 (d, 1 H);4.63 (s, 1 H); 3.73 (s, 3 H); 1.36 (s, 3 H); 1.33 (s, 3 H). 53-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-N-(methylsulfonyl)-3- phenylpropanamide

MeSO₂NH₂ 467 B 6 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (trifluoromethylsulfonyl) propanamide

CF₃SO₂NH₂ 520 B 7 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-N-neopentyl-3- phenylpropanamide

458 B 8 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(2,2,2- trifluoroethyl)prop-anamide

470 B 9 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(3,3,3- trifluoropropyl)- propanamide

484 B 10 ethyl 5-(3-(1-(4- fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3- phenylprop-anamido)-1,3,4-thiadiazole-2-carboxylate

544 B 11 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiophen-3- yl)propanamide

470 B 12 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-N-(4-methylthiazol-2-yl)-3- phenylpropan-amide

485 B 13 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1H-1,2,4- triazol-3-yl)propanamide

455 B 14 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1H-tetrazol-5- yl)propanamide

456 B 15 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-N-(5-hydroxy-1H-pyrazol-3-yl)- 2,2-dimethyl-3- phenylpropanamide

470 B 16 N-(4-cyano-1H-pyrazol-3- yl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-3- phenylpropanamide

479 B 17 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-N-(5-methylthiazol-2-yl)-3- phenylpropanamide

485 B 18 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-N-(5-methyl-1,3,4- thiadiazol-2-yl)-3- phenylpropanamide

486 B 19 N-(3-cyanothiophen-2-yl)- 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl- 3-phenylpropanamide

495 B 20 N-(5-ethyl-1,3,4-thiadiazol- 2-yl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-3-phenylpropanamide

500 B 21 N-(5-cyclopropyl-1,3,4- thiadiazol-2-yl)-3-(1-(4-fluorophenyl)-1H-indazole- 5-yl)-2,2-dimethyl-3- phenylpropanamide

512 B 22 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-N-(5-(methylthio)-1,3,4- thiadiazol-2-yl)-3- phenylpropanamide

518 B 23 N-(benzyl[d]thiazol-2-yl)-3- (1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl- 3-phenylpropanamide

521 B 24 N-(4,5-dimethylthiazol-2- yl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-3- phenylpropanamide

499 B 25 3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(5- (trifluoromethyl)-1,3,4- thiadiazol-2- yl)propanamide

540 B 26 N-(5-chlorothiazol-2-yl)-3- (1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl- 3-phenylpropanamide

505 B 27 ethyl 2-(3-(1-(4- fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3- phenylpropanamido)thiazol- 4-carboxylate

543 B 28 ethyl 2-(2-(3-(1-(4- fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3- phenylpropanamido)thiazol- 4-yl)acetate

557 B

Example 293-(1H-Indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide

The procedure of Scheme B was used in preparing the Example 29 compound.

-   (a) (1H-Indazol-5-yl)methanol (17.3 g, 117 mmol) from experimental    (1c) was dissolved in 1 L dry DCM and Dess-Martin periodinane (53 g,    125 mmol) was added portionwise and the reaction was stirred    overnight. The next day, the reaction was extracted with 1 M NaOH×3.    The aqueous layers were pooled and extracted with EtOAc×5. The    combined organic layers were dried over MgSO₄, filtered,    concentrated in vacuo to give 14.1 g (82% yield) of yellow solid    1H-indazole-5-carbaldehyde. MS found: (M+H)⁺=147.-   (b) To a solution of 1H-indazole-5-carboxaldehyde (28 g, 200 mmol)    and TMEDA (2 m mL) in 1 L of THF was added a solution of 1.0M    phenylmagnesium bromide in THF (800 mmol) dropwise. After 3 days,    the reaction was quenched with sat. NaCl and extracted with 3×EtOAc.    The EtOAc extracts were dried over MgSO₄, filtered, concentrated by    rotary evaporator, and crystallized from CH₂Cl₂/ether to give 28.8 g    (64%) of 1H-indazol-5-yl)(phenyl)methanol. MS found: (M+H)⁺=225.-   (c) To a solution of 1H-indazol-5-yl)(phenyl)methanol (12.1 g, 54    mmol) and 1M TiCl₄ in CH₂Cl₂ (60 mmol) in 200 mL of CH₂Cl₂ and 200    mL of THF at 0° C. was added    (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (50.8 mL, 250    mmol). The reaction was warmed to rt and stirred overnight. The    reaction was quenched with sat NaCl and extracted with 3×CH₂Cl₂. The    CH₂Cl₂ extracts were dried over MgSO₄, filtered, concentrated by    rotary evaporator, and chromatographed on SiO₂ using EtOAc/hexanes    (1:2) to give 11.1 g (66%) of Methyl    3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate. MS found:    (M+H)⁺=309.-   (d) Methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (2.5    g, 8.1 mmol) was dissolved in 50 mL of DMSO, 50 mL of 1 NaOH and 50    mL of MeOH and heated at 100° C. overnight. The reaction was    quenched with sat. NaCl and extracted with 2×EtOAc. The EtOAc    extracts were dried over MgSO₄, filtered, and concentrated by rotary    evaporator to give 2.4 g of    3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid. MS found:    (M+H)⁺=295.-   (e) 3-(1H-Indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (44 mg,    0.15 mmol) and 2-aminothiazole using General Coupling Method A to    give 22 mg (39% yield) of Example 29. MS found: (M+H)⁺=377. 400 MHz    ¹H-NMR (DMSO-d6) δ 12.9 (br s, 1H); 11.9 (s, 1H); 7.94 (s, 1H); 7.70    (s, 1H); 7.35 d, 1H); 7.31 (t, 3H); 7.18 (t, 3H); 7.09 (t, 1H); 7.05    (d, 1H); 4.94 (s, 1H); 1.24 (s, 6H).

Example 303-(1H-Indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

The title compound was prepared from3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (Example 29(d))(44 mg, 0.15 mmol) and 2-amino-1,3,4-thiadiazole using General CouplingMethod A to give 29 mg (51% yield) of Example 30. MS found: (M+H)⁺=378.

Example 313-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(thiazol-2-yl)propanamide

The title compound was prepared following the procedure in Scheme C.

-   (a) A solution of 1-(4-fluorophenyl)-1H-indazole-5-carbaldehyde (1.0    g, 4.17 mmol) from experimental (1e) in 30 mL DCM was cooled to −78    C and treated with TiCl₄ (4.2 mL of 1.0 M solution in DCM). The    reaction was warmed to rt and treated with    1-methoxy-2-methyl-1-(trimethylsiloxy)propene (799 mg, 4.58 mmol),    stirred for 1 h, and quenched with sat NaHCO₃. The mixture was    extracted 2×EtOAc, sat NH₄Cl was added to the aqueous layer and then    extracted 1×EtOAc. Dried organic layers with MgSO₄, filtered, conc,    and chromatographed on SiO₂ using 25% EtOAc in hexanes. Obtained 820    mg (57%) of white solid methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2-dimethylpropanoate.    MS found: (M+H)⁺=343.-   (b) Methyl 3 -(1-(4-fluorophenyl)-1H-indazol-5-yl)-3    -hydroxy-2,2-dimethylpropan-oate (250 mg, 0.73 mmol) was taken up in    DCM and treated with 10 mg DMAP followed by thiocarbonyldiimidazole    (650 mg, 3.65 mmol). Stirred at rt for 72 h, extracted from brine    1×DCM and 2×EtOAc. Then combined organic layers were dried over    MgSO₄, filtered, conc. and then dissolved in 40 mL dry toluene.-   (c) Tributyltin hydride (637 mg, 2.19 mmol) was added followed by    AIBN (36 mg, 0.22 mmol) and the reaction was refluxed for 3 h. The    reaction was concentrated in vacuo, extracted from brine with    EtOAc×2, dried over MgSO₄, filtered, and conc. The residue was    purified by HPLC to give 151 mg (63% yield) of deoxygenated compound    methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate. MS    found: (M+H)⁺=327.-   (d) Methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate was    dissolved in 5:1 MeOH/DMSO (12 mL) and treated with 3 mL 1 M NaOH    and heated at 85 C overnight. The next day, the reaction was    acidified with TFA and purified by HPLC to give 52 mg of a colorless    oil 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic    acid. MS found: (M+H)⁺=313.-   (e) 3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic    acid (26 mg, 0.08 mmol) was coupled to 2-aminothiazole using General    Coupling Method A to give 20 mg (61% yield) of Example 31. MS found:    (M+H)⁺=395.

Example 323-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4-thiadiazol-2-yl)propanamide

3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic acid (26mg, 0.08 mmol) from Example 31(d) was coupled to2-amino-1,3,4-thiadiazole using General Coupling Method A to give 21 mg(61% yield) of Example 32. MS found: (M+H)⁺=396.

The Scheme D procedure was used in preparing the Examples 33 to 39compounds.

Example 333-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethyl-N-(thiazol-2-yl)hexanamide

-   (a) To a solution of 1-(4-fluorophenyl)-1H-indazole-5-carboxaldehyde    (100 mg, 0.416 mmol) from experimental (1e) in 5 mL of THF was added    a solution of 2.0M isobutylmagnesium bromide in THF (0.5 mmol)    dropwise. After 1 hr, the reaction was quenched with sat. NH₄Cl and    extracted with 2×EtOAc. The EtOAc extracts were dried over MgSO₄,    filtered, and concentrated by rotary evaporator to give    1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol. MS found:    (M+H)⁺=299.-   (b) To a solution of    1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol (0.41    mmol) in 20 mL of CH₂Cl₂ at 0° C. was added 1M TiCl₄ in CH₂Cl₂ (0.5    mmol) all at once. After 30 min,    (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.24 mL, 1.2    mmol) was added and the reaction was warmed to rt and stirred    overnight. The reaction was quenched with water and extracted with    CH₂Cl₂. The CH₂Cl₂ extracts were dried over MgSO₄, filtered, and    concentrated by rotary evaporator to give methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoate. MS    found: (M+H)⁺=383.-   (c) Methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoate (0.4    mmol) was dissolved in 5 mL of DMSO, 10 mL of 1 NaOH and 5 mL of    MeOH and heated at 100° C. overnight. The reaction was quenched with    sat. KH₂PO₄ and extracted with 2×EtOAc. The EtOAc extracts were    dried over MgSO₄, filtered, and concentrated by rotary evaporator to    give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoic    acid. MS found: (M+H)⁺=369.-   (d) 3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoic    acid (0.2 mmol) was coupled with thiazol-2-amine (33 mg, 0.3 mmol)    using General Coupling Method A. The product was purified by HPLC to    give 52 mg (58%) of the desired product Example 33. MS found:    (M+H)⁺=451.

Example 343-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethyl-N-(1,3,4-thiadiazol-2-yl)hexanamide

To a solution of3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoic acid (220mg, 0.6 mmol) from Example 33(c) was coupled to 1,3,4-thiadiazol-2-amine(60 mg, 0.6 mmol) using General Coupling Method B. The product waspurified by HPLC to give 33 mg (24%) of the desired product Example 34.MS found: (M+H)⁺=452. NMR(CDCl₃) δ 8.73 (s, 1H); 8.11 (s, 1H); 7.8-8.4(bs, 1H) 7.55-7.61 (m, 3H); 7.49-7.51 (d, 1H); 7.28-7.30 (d, 1H);7.14-7.19 (m, 3H); 3.31-3.36 (dd, 1H), 1.88-1.95 (dt, 1H); 1.26 (s, 3H);1.15(s, 3H); 0.6-0.8 (dd, 6H).

Example 353-Cyclopentyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(thiazol-2-yl)propanamide

-   (a) To a solution of a solution of 2.0M cyclopentylmagnesium bromide    in THF (8.0 mmol) was added    1-(4-fluorophenyl)-1H-indazole-5-carbaldehyde (200 mg, 0.832 mmol)    from experimental (1e) in 5 mL of THF dropwise. After 1 hr, the    reaction was quenched with sat. NH₄Cl and extracted with 2×EtOAc.    The EtOAc extracts were dried over MgSO₄, filtered, concentrated by    rotary evaporator, and chromatographed on SiO₂ using EtOAc/hexanes    (1:3) to give 75 mg of cyclopentyl    (1-(4-fluorophenyl)-1H-indazol-5-yl)methanol. MS found: (M+H)⁺=311.-   (b) To a solution of cyclopentyl    (1-(4-fluorophenyl)-1H-indazol-5-yl)methanol (75 mg, 0.24 mmol) in    20 mL of CH₂Cl₂ at 0° C. was added 1M TiCl₄ in CH₂Cl₂ (0.5 mmol) all    at once. After 30 min,    (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.2 mL, 1.0 mmol)    was added and the reaction was warmed to rt and stirred overnight.    The reaction was quenched with water and extracted with CH₂Cl₂. The    CH₂Cl₂ extracts were dried over MgSO₄, filtered, and concentrated by    rotary evaporator to give 80 mg of methyl    3-cyclopentyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate.    MS found: (M+H)⁺=395.-   (c) Methyl    3-cyclopentyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate    (80 mg, 0.2 mmol) was dissolved in 5 mL of DMSO, 10 mL of 1 NaOH and    5 mL of MeOH and heated at 100° C. overnight. The reaction was    quenched with sat. KH₂PO₄ and extracted with 2×EtOAc. The EtOAc    extracts were dried over MgSO₄, filtered, and concentrated by rotary    evaporator to give    3-cyclopentyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic    acid. MS found: (M+H)⁺=381.-   (d)    3-Cyclopentyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic    acid (40 mg, 0.105 mmol) was coupled with thiazol-2-amine (20 mg,    0.2 mmol) using General Coupling Method A. The product was purified    by HPLC to give 13 mg (31%) of the desired product Example 35. MS    found: (M+H)⁺=463. NMR(CDCl₃) δ 8.19 (s, 1H); 7.92 (bs, 1H)    7.67-7.71 (m, 2H); 7.55-7.59 (m, 2H); 7.22-7.26 (m, 4H); 7.10 (d,    1H); 3.33-3.36 (d, 1H), 2.38-2.43 (m, 1H); 1.63-1.77 (m, 1H);    1.20-1.70 (m, 6H); 1.45 (s, 3H); 0.8-1.0 (m, 2H).

Example 363-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-(pyridin-4-yl)-N-(thiazol-2-yl)propanamide

-   (a) To a solution of a solution of 4-pyridylmagnesium bromide in    THF, which was prepared by treating 4-iodopyridine (590 mg, 2.88    mmol) in 5 mL of THF with 1.5 mL of 2.0M ethylmagnesium bromide at    0° C., was added 1-(4-fluorophenyl)-1H-indazole-5-carbaldehyde (200    mg, 0.832 mmol) in 5 mL of THF dropwise. After 2 hr, the reaction    was quenched with sat. NH₄Cl and extracted with 2×EtOAc. The EtOAc    extracts were dried over MgSO₄, filtered, concentrated by rotary    evaporator, and chromatographed on SiO₂ using EtOAc/hexanes (1:2) to    give 230 mg of    (1-(4-fluorophenyl)-1H-indazol-5-yl)(pyridin-4-yl)methanol. MS    found: (M+H)⁺=320.-   (b) To a solution of    (1-(4-fluorophenyl)-1H-indazol-5-yl)(pyridin-4-yl)methanol (130 mg,    0.407 mmol) in 20 mL of CH₂Cl₂ at 0° C. was added 1M TiCl₄ in CH₂Cl₂    (0.5 mmol) all at once. After 30 min,    (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.2 mL, 1.0 mmol)    was added and the reaction was warmed to rt and stirred overnight.    The reaction was quenched with water and extracted with CH₂Cl₂. The    CH₂Cl₂ extracts were dried over MgSO₄, filtered, concentrated by    rotary evaporator, and chromatographed on SiO₂ using EtOAc/hexanes    (1:1) to give 110 mg of methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-(pyridin-4-yl)propanoate.    MS found: (M+H)⁺=395.-   (c) Methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-(pyridin-4-yl)propanoate    (80 mg, 0.2 mmol) was dissolved in 10 mL of DMSO, 10 mL of 1 NaOH    and 10 mL of MeOH and heated at 100° C. overnight. The reaction was    quenched with sat. NaCl and extracted with 2×EtOAc. The EtOAc    extracts were dried over MgSO₄, filtered, and concentrated by rotary    evaporator to give 95 mg of    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-(pyridin-4-yl)propanoic    acid. MS found: (M+H)⁺=390.-   (d)    3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-(pyridin-4-yl)propanoic    acid (46 mg, 0.11 mmol) was coupled with thiazol-2-amine (22 mg,    0.22 mmol) using General Coupling Method A. The product was purified    by HPLC to give 12 mg (23%) of Example 36. MS found: (M+H)⁺=472.

Example 373-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-(pyridin-4-N-oxide-yl)-N-(thiazol-2-yl)propanamide

-   (a) To a solution of    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-(pyridin-4-yl)propanoic    acid (49 mg, 0.126 mmol, from 36(c)) in 10 mL of CH₂Cl₂ was added    m-chloro-perbenzoic acid (MCPBA) (43 mg, 0.25 mmol). The reaction    was stirred for 2 hr and then concentrated by rotary evaporator to    give crude product    4-(2-carboxy-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methylpropyl)pyridine    1-oxide.-   (b)    4-(2-Carboxy-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methylpropyl)pyridine    1-oxide (0.126 mmol) was coupled with thiazol-2-amine (50 mg, 0.50    mmol) using General Coupling Method A. The product was purified by    HPLC followed by chromatography on SiO₂ using EtOAc/MeOH (85:15) to    give 9 mg (15%) of Example 37. MS found: (M+H)⁺=488.

Example 383-Cyclohexyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(thiazol-2-yl)propanamide

-   (a) To a solution of 2.0M cyclohexylmagnesium bromide in THF (8.0    mmol) was added 1-(4-fluorophenyl)-1H-indazole-5-carbaldehyde (200    mg, 0.832 mmol) in 5 mL of THF dropwise. After 1 hr, the reaction    was quenched with sat. NH₄Cl and extracted with 2×EtOAc. The EtOAc    extracts were dried over MgSO₄, filtered, and concentrated by rotary    evaporator to give    cyclohexyl(1-(4-fluorophenyl)-1H-indazol-5-yl)methanol. MS found:    (M+H)⁺=325.-   (b) To a solution of    cyclohexyl(1-(4-fluorophenyl)-1H-indazol-5-yl)methanol (0.83 mmol)    in 20 mL of CH₂Cl₂ at 0° C. was added 1M TiCl₄ in CH₂Cl₂ (1.6 mmol)    all at once. After 30 min,    (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.65 mL, 3.2    mmol) was added and the reaction was warmed to rt and stirred    overnight. The reaction was quenched with water and extracted with    CH₂Cl₂ The CH₂Cl₂ extracts were dried over MgSO₄, filtered, and    concentrated by rotary evaporator to give methyl    3-cyclohexyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate.    MS found: (M+H)⁺=409.-   (c) Methyl    3-cyclohexyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate    (0.83 mmol) was dissolved in 20 mL of DMSO, 20 mL of 1 NaOH and 20    mL of MeOH and heated at 100° C. overnight. The reaction was    quenched with sat. NaCl and extracted with 2×EtOAc. The EtOAc    extracts were dried over MgSO₄, filtered, and concentrated by rotary    evaporator to give 78 mg of    3-cyclohexyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic    acid. MS found: (M+H)⁺=381.-   (d)    3-Cyclohexyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic    acid (78 mg, 0.2 mmol) was coupled with thiazol-2-amine (50 mg, 0.5    mmol) using General Coupling Method A. The product was purified by    HPLC to give 18 mg (19%) of the desired product Example 38. MS    found: (M+H)⁺=477.

Example 393-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(thiazol-2-yl)pentanamide

-   (a) To a solution of a solution of 1.0M ethylmagnesium bromide in    THF (1.0 mmol) was added    1-(4-fluorophenyl)-1H-indazole-5-carbaldehyde (120 mg, 0.5 mmol) in    10 mL of THF dropwise. After 1 hr, the reaction was quenched with    sat. NH₄Cl and extracted with 2×EtOAc. The EtOAc extracts were dried    over MgSO₄, filtered, concentrated by rotary evaporator, and    chromatographed on SiO₂ using EtOAc/hexanes (1:1) to give 120 mg of    1-(1-(4-fluorophenyl)-1H-indazol-5-yl)propan-1-ol. MS found:    (M+H)⁺=271.-   (b) To a solution of    1-(1-(4-fluorophenyl)-1H-indazol-5-yl)propan-1-ol (120 mg, 0.44    mmol) in 10 mL of CH₂Cl₂ at 0° C. was added 1M TiCl₄ in CH₂Cl₂ (1.0    mmol) all at once. After 30 min,    (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.2 mL, 1.0 mmol)    was added and the reaction was warmed to rt and stirred overnight.    The reaction was quenched with water and extracted with CH₂Cl₂. The    CH₂Cl₂ extracts were dried over MgSO₄, filtered, and concentrated by    rotary evaporator to give methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpentanoate. MS    found: (M+H)⁺=355.-   (c) Methyl    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpentanoate (0.44    mmol) was dissolved in 5 mL of DMSO, 10 mL of 1 NaOH and 5 mL of    MeOH and heated at 100° C. overnight. The reaction was quenched with    sat. KH₂PO₄ and extracted with 2×EtOAc. The EtOAc extracts were    dried over MgSO₄, filtered, and concentrated by rotary evaporator to    give 130 mg of    3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpentanoic acid.    MS found: (M+H)⁺=341.-   (d) 3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpentanoic    acid (68 mg, 0.2 mmol) was coupled with thiazol-2-amine (33 mg, 0.3    mmol) using General Coupling Method A. The product was purified by    HPLC to give 13 mg (15%) of Example 39. MS found: (M+H)⁺=423.    NMR(CDCl₃) δ 8.2 (s, 1H); 7.74 (s, 1H); 7.67-7.70 (m, 1H); 7.55-7.67    (m, 2H); 7.42-7.45 (m, 1H); 7.21-7.26 (m, 3H); 7.10 (d, 1H);    3.28-3.31 (dd, 1H), 1.88-1.97 (m, 1H); 1.50-1.56, (m, 1H); 1.34 (s,    3H); 1.21 (s, 3H); 0.6-0.8 (t, 3H).

Examples 40 to 56

Examples 40 to 56 in the Table below were prepared using the same methodas used for Examples 33 to 39 with the M-M_(a)-MgBr reagent shown in thetable.

Ex. Name Product Structure M-M_(a)-MgBr (M + H)+ 403-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(thiazol-2-yl)-3-o- tolylpropanamide

2-methyl-phenyl 485 41 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(thiazol-2-yl)-3-m- tolylpropanamide

3-methyl-phenyl 485 42 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(thiazol-2-yl)-3-p- tolylpropanamide

4-methyl-phenyl 485 43 3-(3-fluorophenyl)-3-(1-4-fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-N-(thiazol-2-yl)propanamide

3-fluoro-phenyl 489 44 3-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-N-(thiazol-2-yl)propanamide

4-fluoro-phenyl 489 45 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4-thiadazol-2- yl)hex-5-enamide

allyl 436 46 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4-thiadazol-2- yl)hexanamide

propyl 438 NMR (CDCl₃) δ 8.8 (s, 1 H); 8.17 (d, 1 H) 7.64-7.68 (m, 3 H);7.57-7.59 (d, 1 H); 7.34-7.36 (dd, 1 H); 7.22-7.26 (m, 2 H); 3.29-3.32(dd, 1 H), 1.90-1.96 (m, 1 H); 1.40-1.50 (m, 1 H); 1.38 (s, 3 H); 1.23(s, 3 H); 1.0-1.14 (m, 2 H); 0.8 (t, 3 H). 473-cyclopropyl-3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4-thiadiazol-2-yl)propanamide

cyclopropyl 436 48 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,4-trimethyl-N-(1,3,4-thiadiazol-2- yl)pentanamide

isopropyl 438 NMR (CDCl₃) δ 8.81 (s, 1 H); 8.21 (d, 1 H) 7.84 (s, 1 H);7.65-7.70 (m, 2 H); 7.61-7.62 (d, 1 H); 7.47-7.50 (d, 1 H); 7.23-7.27(m, 2 H); 3.22-3.24 (d, 1 H), 2.26-2.31 (m, 1 H); 1.52 (s, 3 H); 0.97(s, 3 H); 0.90-0.92 (d, 3 H); 0.69-0.71 (d, 3 H). 493-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4-thiadiazol-2-yl)- 3-o-tolylpropanamide

2-methyl-phenyl 486 50 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4-thiadiazol-2-yl)- 3-m-tolylpropanamide

3-methyl-phenyl 486 51 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4-thiadiazol-2-yl)- 3-p-tolylpropanamide

4-methyl-phenyl 486 52 3-(3-fluorophenyl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-N-(1,3,4-thiadiazol-2-yl)propanamide

3-fluoro-phenyl 490 53 3-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-N-(1,3,4-thiadiazol-2-yl)propanamide

4-fluoro-phenyl 490 54 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethyl-N-(1,3,4-thiadiazol-2- yl)hex-5-enamide

2-methylallyl 450 55 (E)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4-thiadiazol- 2-yl)hept-5-enamide

but-2-enyl 450 56 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethyl-N-(1,3,4-thiadiazol-2- yl)hex-4-enamide

(2-methylprop- 1-enyl) 450

Alkylation of Indazoles, General Procedure A

Shell vials were charged with methyl3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanate (150 mg, 0.49 mmol)in 2 mL THF and NaH (69 mg of 60% oil immersed, 1.8 mmol) was addedunder N₂. After foaming subsided (about 10 min), the alkylating agent(2.24 mmol, 4.6 equiv) was added neat and the reactions were heated toreflux for 16 hr. The reactions were cooled, concentrated by rotaryevaporation, diluted with 2 mL DMSO, 1 mL MeOH, and 1 mL 5M NaOH andheated for another 16 hr. The crude N-alkylated acids were purified byHPLC and lyophilized to give pure acids which were confirmed by LC-MSand then coupled to a Z—Z_(a)—NH₂ amine using General Coupling Method A.The alkylation reactions gave mixtures of the N-1 and N-2 alkylatedindazoles (typically in a 1:1-3:1 ratio favoring N-1) which could beseparated by HPLC at the acid stage (and coupled independently) orseparated at the final amide stage after coupling.

Alkylation of Indazoles, General Procedure B

Shell vials were charged with methyl3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanate (150 mg, 0.49 mmol)in 2 mL dry DMSO followed by NaN(TMS)₂ (0.73 mmol, 730 uL of 1.0 M THFsolution) under N₂. The orange solutions were treated with alkylator(0.73 mmol, 1.5 equiv) and heated to 85° C. for 72 hr. The reactionswere cooled, concentrated by rotary evaporation, diluted with 2 mL DMSO,1 mL MeOH, and 1 mL 5M NaOH and heated for another 16 hr. The crudeN-alkylated acids were purified by HPLC and lyophilized to give pureacids which were coupled to a Z—Z_(a)—NH₂ amine using General CouplingMethod A. The alkylation reactions gave mixtures of the N-1 and N-2alkylated indazoles which could be separated by HPLC at the acid stage(and coupled independently) or separated at the final amide stage aftercoupling.

Examples 57 to 78

The procedures of Scheme E (General Procedure A) or Scheme F (GeneralProcedure B) were employed to prepare the Examples 57 to 78 compounds.

(M + Ex. Name Product Structure Alkylating Agent Method H)⁺ 573-(1-(2-hydrox-ethyl)- 1H-indazol-5-yl)-2,2- dimethyl-3-phenyl-N-(thiazol-2- yl)propanamide

TBSOCH₂CH₂Br¹ B 421 58 2,2-dimethyl-3-phenyl- 3-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol- 5-yl)-N-(thiazol-2- yl)propanamide

A 461 400 MHz ¹H-NMR (DMSO-d6) δ 11.9 (s, 1 H); 7.98 (s, 1 H); 7.72 (s,1 H); 7.38 (d, 1 H); 7.38 (d, 1 H); 7.31 (d, 2 H); 7.20 (m, 3 H); 7.08(d, 1 H); 7.07 (d, 1 H); 4.97 (s, 1 H); 4.72 (m, 1 H); 3.93 (dd, 2 H);3.48 (app t, 2 H); 2.05 (m, 2 H); 1.8 (dd, 2 H); 1.27 (s, 6 H). 592,2-dimethyl-3-(1-(1- methylpiper-idin-4-yl)- 1H-indazol-5-yl)-3-phenyl-N-(thiazol-2- yl)propanamide

A 474 60 2,2-dimethyl-3-(1- (methylsulfonylmethyl)- 1H-indazol-5-yl)-3-phenyl-N-(thiazol-2- yl)propanamide

A 469 61 3-(1-isopropyl-1H- indazol-5-yl)-2,2- dimethyl-3-phenyl-N-(thiazol-2- yl)propanamide

2-iodopropane A 419 400 MHz ¹H-NMR (DMSO-d6) δ 12.0 (s, 1 H); 7.98 (s, 1H); 7.74 (s, 1 H); 7.53 (d, 1 H); 7.41 (d, 1 H); 7.35 (d, 2 H); 7.23 (m,3 H); 7.14 (m, 2 H); 5.00 (s, 1 H); 4.88 (m, 1 H); 1.43 (d, 6 H); 1.30(s, 6 H). 62 3-(2-isopropyl-2H- indazol-5-yl)-2,2- dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2- yl)propanamide

2-iodopropane A 419 400 MHz ¹H-NMR (DMSO-d6) δ 11.9 (s, 1 H); 8.32 (s, 1H); 7.67 (s, 1 H); 7.41 (m, 2 H); 7.33 (d, 2 H); 7.23 (t, 2 H); 7.21 (t,1 H); 7.11 (d, 1 H); 7.08 (dd, 1 H); 4.96 (s, 1 H); 4.73 (m, 1 H); 1.52(d, 6 H); 1.30 (d, 6 H). 63 3-(1-isopropyl-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

2-iodopropane A 420 64 2,2-dimethyl-3-(1- (methylsulfonylmethyl)-1H-indazol-5-yl)-3- phenyl-N-(1,3,4- thiadiazol-2- yl)propanamide

A 470 65 3-(1-(2-hydroxyethyl)- 1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

TBSOCH₂CH₂Br¹ B 422 66 3-(1-isopentyl-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

B 448 67 3-(2-isopentyl-2H- indazol-5-yl)-2,2- dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2- yl)propanamide

B 448 68 3-(1-butyl-1H-indazol- 5-yl)-2,2-dimethyl-3- phenyl-N-(1,3,4-thiadiazol-2- yl)propanamide

iodobutane B 434 69 3-(2-(3-methoxy- propyl)-2H-indazol-5-yl)-2,2-dimethyl-3- phenyl-N-(1,3,4- thiadiazol-2- yl)propanamide

B 450 70 3-(1-isobutyl-1H- indazol-5-yl)-2,2- dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2- yl)propanamide

B 434 71 3-(1-(3- methoxypropyl-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

B 450 72 3-(1-benzyl-1H- indazol-5-yl)-2,2- dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2- yl)propanamide

benzyl bromide B 468 73 3-(2-benzyl-2H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

benzyl bromide B 468 74 2,2-dimethyl-3-(1- phenethyl-1H-indazol-5-yl)-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

bromoethyl benzene B 482 75 3-(1-(3-hydroxypropyl)-1H-indazol-5-yl)-2,2- dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2-yl)propanamide

TBSO(CH₂)₃Br¹ B 436 76 3-(1-(4-hydroxybutyl)- 1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

TBSO(CH₂)₄Br¹ B 450 77 3-(2-(4-hydroxybutyl)- 2H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

TBSO(CH₂)₄Br¹ B 450 78 3-(1-cycloheptyl-1H- indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

bromo- cycloheptane B 474 ¹Examples 57, 65, 75, 76, and 77 used at-butyldimethylsilyl oxygen protecting group. During the esterhydrolysis (step c), this group was removed. Amine coupling (step d)proceeded smoothly thereafter. ²Examples 60 and 64 were treated with anadditional step of mCPBA (2 equivs) oxidation of the sulfide to thesulfone after alkylation (step b) was complete. Saponification and aminecoupling proceeded smoothly thereafter.

Arylation of Indazoles, General Procedure C

Methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (150 mg, 0.5mmol) was dissolved in 1 mL dry dioxane in a 5 mL sealed tube vesselfollowed by the addition of and then K₃PO₄ (208 mg, 1.0 mmol),trans-1,2-cyclohexanediamine (6 uL, 0.1 mmol) and Cut (5 mg, 0.05 mmol).After the addition of the aryl iodide (0.54 mmol), the reactor wassealed and heated at 100° C. for 24 h. The reactor was cooled, opened,and the contents were filtered through a disposable frit with EtOAc andconcentrated in vacuo. Each crude intermediate was taken up in 2 mLDMSO, diluted with 1 mL water and 1 mL MeOH, and treated with 2 mL 5 MNaOH and refluxed for 16 h. The following day, each reaction wascarefully acidified with 3 mL TFA and purified by HPLC. The purifiedpenultimate acids (confirmed by MS) were then coupled to a Z—Z_(a)—NH₂amine and purified using General Coupling Method A or B.

Arylation of Indazoles, General Procedure D

3-(1H-Indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide(59 mg, 0.16 mmol) was dissolved in 1 mL dry dioxane in a 5 mL sealedtube vessel followed by the addition of K₃PO₄ (60 mg, 0.28 mmol),trans-1,2-cyclohexanediamine (9 uL, 0.08 mmol) and CuI (3 mg, 0.016mmol). After the addition of the aryl iodide (0.19 mmol), the reactorwas sealed and heated at 110° C. for 24 h. The reactor was cooled,opened, and the contents were filtered through a disposable frit withEtOAc and concentrated in vacuo, acidified with TFA, and purified byHPLC.

Examples 79 to 97

The Examples 79 to 97 compounds were prepared using the procedure ofScheme G (General Procedure C) or Scheme H (General Procedure D).

Ex. Name Product Structure aryl iodide Method (M + H)+ 792,2-dimethyl-3-phenyl-3- (1-(pyridin-2-yl)-1H-indazol-5-yl)-N-(thiazol-2- yl)propanamide

2-iodo-pyridine C 454 80 2,2-dimethyl-3-phenyl-3- (1-(pyridin-2-yl)-1H-indazol-5-yl)-N-(1,3,4- thiadiazol-2- yl)propanamide

2-iodo-pyridine C 455 81 2,2-dimethyl-3-phenyl-3- (1-(pyridin-4-yl)-1H-indazol-5-yl)-N-(thiazol-2- yl)propanamide

4-iodo-pyridine C 454 82 2,2-dimethyl-3-phenyl-3- (1-(pyridin-4-yl)-1H-indazol-5-yl)-N-(1,3,4- thiadiazol-2- yl)propanamide

4-iodo-pyridine C 455 83 3-(1-(4-methoxyphenyl)- 1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2- yl)propanamide

4-methoxy-1- iodobenzene C 484 84 3-(1-(4-hydroxyphenyl)-1H-indazol-5-yl)-2,2- dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2-yl)propanamide

—¹ — 470 85 2,2-dimethyl-3-phenyl-3- (1-(pyridin-3-yl)-1H-indazol-5-yl)-N-(thiazol-2- yl)propanamide

3-iodopyridine C 454 400 MHz ¹H-NMR (DMSO-d6) δ 11.9 (s, 1 H); 8.99 (d,1 H); 8.54 (d, 1 H); 8.38 (s, 1 H); 8.23 (d, 1 H); 7.88 (s, 1 H); 7.75(d, 1 H); 7.62 (dd, 1 H); 7.39 (dd, 1 H); 7.36 (d, 1 H); 7.31 (d, 2 H);7.20 (app t, 2 H); 7.1 (app t, 1 H); 7.07 (d, 1 H); 5.03 (s, 1 H); 1.28(s, 6 H). 86 2,2-dimethyl-3-phenyl-3- (1-(pyridin-3-yl)-1H-indazol-5-yl)-N-(1,3,4- thiadiazol-2- yl)propanamide

3-iodopyridine C 455 87 2,2-dimethyl-3-phenyl-3- (1-phenyl-1H-indazol-5-yl)-N-(1,3,4-thiadiazol-2- yl)propanamide

iodobenzene D 454 88 methyl 4-(5-(3-(1,3,4- thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1- phenylpropyl)-1H-indazol- 1-yl)benzoate

methyl 4- iodobenzoate D 512 89 4-(5-(3-(1,3,4-thiadiazol-2-ylamino)-2,2-dimethyl-3- oxo-1-phenylpropyl)-1H- indazol-1-yl)benzoicacid

—² D 498 90 2,2-dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2-yl)-3-(1-(4-(trifluoro- methyl)phenyl)-1H- indazol-5-yl)propanamide

4-trifluoro- methylbenzene D 522 91 3-(1-(4-bromophenyl)-1H-indazol-5-yl)-2,2- dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2-yl)propanamide

4-bromo-1- iodobenzene D 533 92 3-(1-(4-fluoro-2-(trifluoromethyl)phenyl)- 1H-indazol-5-yl)-2,2- dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2- yl)proponamide

4-fluoro-2- trifluoromethyl- 1-iodobenzene D 540 933-(1-(4-chlorophenyl)-1H- indazol-5-yl)-2,2- dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2- yl)propanamide

4-chloro-1- iodobenzene D 489 94 3-(1-(3-methoxyphenyl)-1H-indazol-5-yl)-2,2- dimethyl-3-phenyl-N- (1,3,4-thiadiazol-2-yl)propanamide

3-methoxy-1- iodobenzene D 484 95 ethyl 3-(5-(3-(1,3,4-thiadiazol-2-ylamino)-2,2- dimethyl-3-oxo-1- phenylpropyl)-1H-indazol-1-yl)benzoate

Ethyl-3-iodo- benzoate D 526 96 (3S)-3-(1-(4-fluoro-2-methoxyphenyl)-1H- indazol-5-yl)-2,2- dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2- yl)propanamide

4-fluoro- 1-iodo-2- methoxybenzene C 502 97 (3S)-3-(1-(2-cyano-4-fluorophenyl)-1H-indazol- 5-yl)-2,2-dimethyl-3- phenyl-N-(1,3,4-thiadiazol-2- yl)propanamide

2-cyano-4- fluoro-1- iodobenzene C 497 ¹Example 84 was synthesized bythe demethylation of Example 83 (BBr₃, DCM). ²Example 89 came from theester hydrolysis of Example 88 (NaOH, MeOH).

The procedure of Scheme I was used to prepare the Examples 98, 99 and100.

Example 98Trans-2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenyl-N-(thiazol-2-yl)cyclopropanecarboxamide

(a) To a solution of(1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (1.2 g, 3.77 mmol)from experimental (1f) in 200 mL of CH₂Cl₂ was added Dess-MartinPeriodinane (2.0 g, 4.71 mmol) portionwise. After 12 h, the reaction wasquenched with 1M NaOH and extracted with 3×CH₂Cl₂. The CH₂Cl₂ extractswere dried over MgSO₄, filtered, and concentrated by rotary evaporatorto give (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanone in 100%yield. MS found: (M+H)⁺=317.

(b) To a solution of(1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanone (710 mg, 2.24mmol) 20 mL of THF at −78° C. was added 1.6M MeLi in THF (6.4 mmol). Thereaction was warmed to rt and stirred for 2 hr. The reaction wasquenched with water and extracted with 3×EtOAc. The EtOAc extracts weredried over MgSO₄, filtered, and concentrated by rotary evaporator.

(c) The crude residue was dissolved in 10 mL of acetic acid and heatedat 100° C. for 12 h. The reaction was cooled and taken up in 100 mL ofEtOAC then washed with 3×sat. NaHCO₃ The EtOAc extracts were dried overMgSO₄, filtered, concentrated by rotary evaporator, and chromatographedon SiO₂ using EtOAc/hexanes (5:95) to give 500 mg (71%) of1-(4-fluorophenyl)-5-(1-phenylvinyl)-1H-indazole. MS found: (M+H)⁺=309.

(d)(e) To a solution of 1-(4-fluorophenyl)-5-(1-phenylvinyl)-1H-indazole(600 mg, 1.91 mmol) and rhodium(II) acetate dimer (88 mg, 0.2 mmol) in 5mL of diethyl ether was ethyl diazoacetate (1.0 mL, 9.5 mmol) dropwiseover 3 hr. The reaction was stirred for 12 hr. Reaction was incomplete.Added more rhodium acetate and ethyl diazoacetate in the same amount asdescribed above 3 times. The reaction was quenched with sat. NaCl andextracted with 3×EtOAc. The EtOAc extracts were dried over MgSO₄,filtered, and concentrated by rotary evaporator. The crude residue wasdissolved in 20 mL of DMSO, 20 mL of 1 NaOH and 20 mL of MeOH and heatedat 100° C. overnight. The reaction was quenched with sat. KH₂PO₄ andextracted with 2×EtOAc. The EtOAc extracts were dried over MgSO₄,filtered, concentrated by rotary evaporator, and chromatographed on SiO₂using EtOAc/hexanes (1:9 to 1:3) to give a mixture of the cis and transcyclopropyl derivatives. The cis and trans diastereomer were separatedby HPLC to givetrans-2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropanecarboxylicacid andcis-2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropanecarboxylicacid. MS found: (M+H)⁺=373 for both.

(f) A solution oftrans-2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropane-carboxylicacid (120 mg, 0.32 mmol) was coupled with thiazol-2-amine (60 mg, 10mmol) using General Coupling Method B. The product was purified by HPLCto give 65 mg of Example 98. MS found: (M+H)⁺=455.

Example 99Cis-2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenyl-N-(thiazol-2-yl)cyclopropanecarboxamide

Cis-2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropanecarboxylicacid was coupled with thiazol-2-amine (60 mg, 10 mmol) using generalcoupling method B. The product was purified by HPLC to give 45 mg ofExample 99. MS found: (M+H)⁺=455. NMR(MeOD) δ 8.15 (s, 1H); 7.85 (s, 1H)7.64-7.66 (m, 2H); 7.52 (d, 1H); 7.38-7.41 (m, 4H); 7.25-7.29 (m, 4H);7.18 (t, 1H); 7.0 (d, 1H); 2.9 (t, 1H), 2.37 (t, 1H); 1.80 (dd, 1H).

Example 100 Cis andtrans-2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-isobutyl-N-(thiazol-2-yl)cyclopropanecarboxamide

This compound was prepared using the exact same route as was used forExamples 98 and 99. The reaction started with1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol (Scheme I,M_(a)−M=iBu; prepared in Example 33(a)). MS found: (M+H)⁺=435.

Example 1012-(1-(1-(4-Fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(a) Commercially available 5-aminoindazole (6.2 g, 46.6 mmol) wasdissolved in 40 mL dry dioxane in a stainless steel bomb. Under ablanket of N₂ was added trans-1,2-diaminocyclohexane (2.8 mL, 23.3mmol), CuI (890 mg, 4.66 mmol), 1-fluoro-4-iodobenzene (10.3 g, 46.6mmol), and K₃PO₄ (17.8 g, 83.9 mmol). The reactor was sealed and heatedto 110° C. for 16 h. The crude reaction was extracted from a mixture ofNH₄OH/NH₄Cl with EtOAc×3. The combined organic layers were dried overMgSO₄, filtered, concentrated in vacuo, and purified using a 330 g SiO₂MPLC column with EtOAc. Obtained 8.11 g of red solid1-(4-fluorophenyl)-1H-indazol-5-amine. MS found: (M+H)⁺=228.

(b)(c) 1-(4-Fluorophenyl)-1H-indazol-5-amine (4.0 g, 17.6 mmol) wassuspended in 6 M HCl and 20 mL dioxane. Sodium nitrite (1.22 g, 17.6mmol) dissolved in 15 mL water was added portionwise. After 1 h,potassium iodide dissolved in 10 mL water was added and after 6 h,additional KI (1.46 g) was added. After a total of 18 h, the reactionwas carefully quenched with sat. sodium metabisulfite and extracted withether ×3. The organic layers were dried with MgSO₄, concentrated invacuo, filtered, and chromatographed on a 330 g SiO₂ MPLC column using25% EtOAc in hexanes. Obtained 2.1 g (35%) of off-white solid1-(4-fluorophenyl)-5-iodo-1H-indazole. MS found: (M+H)⁺=339.

(d) 1-(4-Fluorophenyl)-5-iodo-1H-indazole (2.0 g, 5.9 mmol) wasdissolved in dry THF (30 mL), cooled to −78° C., and treated with nBuLi(4 mL, 1.6 M in hexanes, 6.5 mmol). After 1 h, cyclohexanone (919 uL,8.88 mmol) was added all at once and the reaction was allowed to warm tort. The crude reaction was extracted from water using EtOAc and thecombined organic layers were dried with MgSO₄, concentrated in vacuo,filtered, and chromatographed on a SiO₂ MPLC column using 25% EtOAc inhexanes. Obtained 700 mg (38%) of1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexanol. MS found:(M+H)⁺=311.

(e) To a solution of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexanol(500 mg, 1.6 mmol) in DCE (20 mL) was added1-methoxy-2-methyl-1-trimethylsiloxy-propene (935 uL, 4.8 mmol) followedby TiCl₄ (1.7 mL of 1.0 M in DCM). Within 10 min, the reaction wascomplete. The reaction was quenched with MeOH and then extracted frombrine containing dilute HCl with EtOAc×4. The organic layers were driedover MgSO₄, filtered, concentrated and purified on SiO₂ using 25% EtOAcin hexanes to give 635 mg (100%) of methyl2-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methylprop-anoateMS found: (M+H)⁺=395.

(f) Methyl2-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methylpropanoate(635 mg, 1.61 mmol) was dissolved in 4 mL pyridine and transferred to amicrowave reactor. Potassium cyanide (419 mg, 6.45 mmol) and LiI (864mg, 6.45 mmol) were added and the reactor was sealed under nitrogen andheated in a microwave for 30 min at 180° C. The reaction was extractedfrom 1 M HCl using EtOAc×4 (lots of black, insoluble precipitate). Theorganic layers were dried, concentrated, and purified by MPLC on SiO₂using 1:1 EtOAc/hexanes. Obtained 115 mg (19%) of off white powder2-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methylpropanoicacid.

(g)2-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methylpropanoicacid (27 mg, 0.07 mmol) was coupled with 2-amino-1,3,4-thiadiazole usingGeneral Coupling Method B. The product was purified by HPLC to give 2 mgof Example 101. MS found: (M+H)⁺=464.

Example 1022-(1-(1-(4-Fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methyl-N-(thiazol-2-yl)propanamide

2-(1-(1-(4-Fluorophenyl)-1H-indazol-5-yl)cyclohexyl)-2-methylpropanoicacid (53 mg, 0.14 mmol) was coupled with 2-aminothiazole using GeneralCoupling Method B. The product was purified by HPLC to give 20 mg ofExample 102. MS found: (M+H)⁺=463. NMR (DMSO-d6) δ 11.0 (s, 1H); 8.26(s, 1H) 7.68-7.72 (m, 3H); 7.58-7.61 (d, 1H); 7-33-7.40 (m, 3H);7.27-7.29 (dd, 1H); 7.13-7.14 (dd, 1H); 2.5-2.6 (m, 2H); 1.40-1.60 (m,4H); 1.30-1.38 (m, 1H) 1.0-1.15 (m, 9H).

Example 1032-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-N-(thiazol-2-yl)cyclopropanecarboxamide

(a) To solution of trimethylphosphonoacetate (2.4 mL, 15 mmol) in DMF(20 mL) was added 1M NaHMDS/THF solution (15 mL, 15 mmol). Afterstirring 30 minutes, a solution of1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (2.4 g, 10 mmol) wasadded and the reaction mixture was stirred overnight. The reaction wasquenched with sat. NaCl and extracted with EtOAc×3. The organic layerswere dried over MgSO₄, filtered, and concentrated to give 2.64 g (89%yield) of product (E)-methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)acrylate. MS found: (M+H)⁺=297.

(b) To solution of trimethylsulfoxonium iodide (440 mg, 2.0 mmol) inDMSO (10 mL) was added a 60% oil dispersion of NaH (80 mg, 2.0 mmol).After stirring 30 minutes, (E)-methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)acrylate (500 mg, 1.69 mmol) wasadded and the reaction mixture was stirred overnight. The reaction wasquenched with sat. NaCl and extracted with EtOAc×3. The organic layerswere dried over MgSO₄, filtered, and concentrated. The crude product waschromatographed on SiO₂ using 1:4 EtOAc/hexanes to give 83 mg (16%yield) of desired product methyl2-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclopropanecarboxylate. MS found:(M+H)⁺=311.

(c) The solid was dissolved in MeOH (10 mL) and DMSO (10 mL) and treatedwith 1 M NaOH (10 mL) at 100° C. After stirring overnight, the MeOH wasremoved in vacuo, the residue acidified with conc HCl to pH 4-5 andextracted with EtOAc×3. The organic layer was dried with MgSO₄,filtered, concentrated in vacuo to give 71 mg (90% yield) of2-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclopropanecarboxylic acid. MSfound: (M+H)⁺=297.

(d) Example 103 was prepared from2-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclopropanecarboxylic acid (34mg, 0.115 mmol) and 2-aminothiazole using General Coupling Method B togive 3 mg (7% yield). MS found: (M+H)⁺=379.

The procedure of Scheme L was used to prepare Examples 104 and 105.

Example 1042-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-N-(thiazol-2-yl)cyclopropanecarboxamide

The procedure of Scheme L was used in preparing the Examples 104 and105.

(a) Following the general procedure of Sun et al (J. Org. Chem. 1997,62, 5627-5629), 4-amino-2-isopropyl-5-methylphenol (7.7 g, 51.2 mmol)was dissolved in dry chloroform (150 mL) followed by potassium acetate(10 g, 102 mmol), and acetic anhydride (15.6 g, 153 mmol). After 2 h,the reaction was refluxed for 3 h and then cooled to rt and stirredovernight.

(b) The next day, 18-crown-6 ether (0.702 g, 2.65 mmol) was addedfollowed by isoamyl nitrite (13.5 g, 115 mmol). The reaction wasrefluxed for 20 h, cooled to rt, washed with sat NaHCO₃, and the organiclayer was dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude product was purified by SiO₂ chromatography eluting with 25% EtOAcin hexane to give 4.74 g of 1-acetyl-6-isopropyl-1H-indazol-5-ylacetate. MS found: (M+H)⁺=261.

(c) The solid was dissolved in MeOH (20 mL) and treated with 1 M NaOH(20 mL). After stirring overnight, the MeOH was removed in vacuo, theresidue acidified with conc HCl to pH 4-5 and extracted with EtOAc×3.The organic layer was dried with MgSO₄, filtered, concentrated in vacuoto give 6-isopropyl-1H-indazol-5-ol.

(d) 6-Isopropyl-1H-indazol-5-ol was dissolved in 20 mL dry dioxane in astainless steel pressure tube. Trans-1,2-cyclohexanediamine (0.35 mL,2.88 mmol) was added followed by CuI (110 mg, 0.58 mmol) and then K₃PO₄2.2 g, 10.4 mmol). After the addition of 4-fluoro-1-iodobenzene (0.7 mL,6.0 mmol), the reactor was sealed and heated at 100 C for 24 h. Thereactor was cooled and the contents were taken up in EtOAc, filteredthrough a SiO₂ plug using EtOAc as the eluent and concentrated in vacuo.The crude product was chromatographed on SiO₂ using 1:3 EtOAc/hexanes togive 453 mg (29% yield) of1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-ol. MS found: (M+H)⁺=271.

(e) 1-(4-Fluorophenyl)-6-isopropyl-1H-indazol-5-ol (270 mg, 1.0 mmol)was dissolved in DCM (5 mL) and pyridine (0.08 mL, 1 mmol) was addedfollowed by triflic anhydride (0.18 mL, 1.1 mmol). After 1 h, thereaction was washed with 1 M HCl and the aqueous layer was dried overMgSO₄, filtered, and concentrated. The crude1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yltrifluoromethanesulfonatewas taken up in 2 mL DMF, transferred to a stainless steel pressurebomb, and dppp (12 mg, 0.03 mmol), triethylamine (0.28 mL, 2 mmol), andPd(OAc)₂ (7 mg, 0.03 mmol) were added. CO (g) was bubbled through for 15minutes then the reaction vessel was sealed and heated at 70° C. for 12h. The reaction was cooled, diluted with EtOAc, washed with brine, andthe organic phase was dried over MgSO₄, filtered, and concentrated. Theresidue was purified on SiO₂ by MPLC using a 1:9 to 1:3 EtOAc/hexanegradient. Obtained 175 mg (56% yield, 2 steps) of methyl1-(4-fluorophenyl)-6-isopropyl-1H-indazole-5-carboxylate. MS found:(M+H)⁺=313.

(f) Methyl 1-(4-fluorophenyl)-6-isopropyl-1H-indazole-5-carboxylate (175mg, 0.56 mmol) was dissolved in 5 mL THF and 1M LiBH₄ in THF (3 mmol)was added. Heated at reflux. After 12 h, the reaction was quenched withMeOH, poured into brine and extracted with EtOAc×3. The organic layerswere dried over MgSO₄, filtered, and concentrated. The residue waspurified on SiO₂ by MPLC using 1:3 EtOAc/hexane. Obtained 148 mg (93%yield) of (1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)methanol. MSfound: (M+H)⁺=285.

(g) (1-(4-Fluorophenyl)-6-isopropyl-1H-indazol-5-yl)methanol (145 mg,0.51 mmol) was dissolved in 5 mL of dry DCM and TiCl₄ (60 mL of 1.0 MDCM solution, 60 mmol) was added portionwise and then stirred 30 min.Then the reaction was treated with1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.2 mL, 1.0 mmol). Thereaction was quenched with aqueous sodium bicarbonate and extracted2×EtOAc, the organic layers dried over MgSO₄, filtered, and concentrate. The residue was purified on SiO₂ by MPLC using a 5:95 to 10:90EtOAc/hexane gradient to give 87 mg (47% yield) of methyl3-(1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)-2,2-dimethylpropanoate.MS found: (M+H)⁺=369.

(h) Methyl3-(1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)-2,2-dimethylpropanoate(87 mg, 0.236 mmol) was heated to 100 C overnight in a mixture of 2 MNaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidifiedto pH 5 with HCl and extracted 2×EtOAc. The organic layers were washedwith water×2, dried over MgSO₄, filtered, and concentrated in vacuo togive 83 mg (99% yield) of acid3-(1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)-2,2-dimethylpropanoicacid. MS found: (M+H)⁺=355.

(i) Example 104 was prepared from3-(1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-yl)-2,2-dimethylpropanoicacid (83 mg, 0.235 mmol) and 1,3,4-thiadiazol-2-amine using GeneralCoupling Method A to give 26 mg (25% yield). MS found: (M+H)⁺=438.

Example 1052-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-N-(thiazol-2-yl)cyclopropanecarboxamide

(a) Following the general procedure of Sun et al (J. Org. Chem. 1997,62, 5627-5629), 4-amino-2-methyl-5-methylphenol (10 g, 72.9 mmol) wasdissolved in dry chloroform (150 mL) followed by potassium acetate (14.3g, 146 mmol), and acetic anhydride (22 g, 219 mmol). After 2 h, thereaction was refluxed for 3 h and then cooled to rt and stirredovernight.

(b) The next day, 18-crown-6 ether (0.962 g, 3.6 mmol) was addedfollowed by isoamyl nitrite (19.2 g, 164 mmol). The reaction wasrefluxed for 20 h, cooled to rt, washed with sat NaHCO₃, and the organiclayer was dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude product was dissolved in MeOH (20 mL) and treated with 1 M NaOH(20 mL). After stirring overnight, the MeOH was removed in vacuo, theresidue acidified with conc HCl to pH 4-5 and extracted with EtOAc×3.The organic layer was dried with MgSO₄, filtered, concentrated in vacuo,and purified on SiO₂ by MPLC eluting with EtOAc to give 5.0 g (46%yield, 2 steps) of 6-methyl-1H-indazol-5-ol. MS found: (M+H)⁺=149.

(c) 6-Methyl-1H-indazol-5-ol (5.0 g, 33.7 mmol) was dissolved in 50 mLdry dioxane in a stainless steel pressure tube.Trans-1,2-cyclohexanediamine (2.0 mL, 17 mmol) was added followed by CuI(647 mg, 3.4 mmol) and then K₃PO₄ 12.7 g, 60 mmol). After the additionof 4-fluoro-1-iodobenzene (3.9 mL, 33.7 mmol), the reactor was sealedand heated at 100 C for 24 h. The reactor was cooled and the contentswere taken up in EtOAc, filtered through a SiO₂ plug with EtOAc andconcentrated in vacuo. The crude product was chromatographed on SiO₂using 1:3 EtOAc/hexanes to give 3.1 g (38% yield) of1-(4-fluorophenyl)-6-methyl-1H-indazol-5-ol. MS found: (M+H)⁺=242.

(d) 1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-ol (500 mg, 1.0 mmol) wasdissolved in DCM (5 mL) and pyridine was added (0.17 mL, 2.1 mmol)followed by triflic anhydride (0.35 mL, 2.1 mmol). After 1 h, thereaction was washed with 1 M HCl and the aqueous layer was dried overMgSO₄, filtered, and concentrated. The crude1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yltrifluoromethanesulfonate wastaken up in 2 mL DMF, transferred to a stainless steel pressure bomb,and dppp (41 mg, 0.10 mmol), triethylamine (0.84 mL, 6 mmol), andPd(OAc)₂ (22 mg, 0.10 mmol) were added. CO₂ (g) was bubbled through for15 minutes then the reaction vessel was sealed and heated at 70° C. for12 h. The reaction was cooled, diluted with EtOAc, washed with brine,and the organic phase was dried over MgSO₄, filtered, and concentrated.The residue was purified on SiO₂ by MPLC and a 1:9 to 1:3 EtOAc/hexanegradient. Obtained 151 mg (26% yield, 2 steps) of methyl1-(4-fluorophenyl)-6-methyl-1H-indazole-5-carboxylate. MS found:(M+H)⁺=285.

(e) Methyl 1-(4-fluorophenyl)-6-methyl-1H-indazole-5-carboxylate (151 g,0.53 mmol) was dissolved in 5 mL THF and 2M LiBH₄ in THF (1 mmol) wasadded. Heated at reflux. After 12 h, the reaction was quenched withMeOH, poured into brine and extracted with EtOAc×3. The organic layerswere dried over MgSO₄, filtered, and concentrated. The residue waspurified on SiO₂ by MPLC using a 1:3 to 1:1 EtOAc/hexane gradient.Obtained 102 mg (75% yield) of(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)methanol. MS found:(M+H)⁺=257.

(f) (1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)methanol (178 mg, 0.51mmol) was dissolved in 5 mL of dry DCM and BF₃—OEt₂ (0.09 mL, 0.7 mmol)was added portionwise and then stirred 30 min. Then the reaction wastreated with 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.43 mL, 2.1mmol). The reaction was quenched with aqueous sodium bicarbonate andextracted 2×EtOAc, the organic layers dried over MgSO₄, filtered, andconcentrate. The residue was purified on SiO₂ by MPLC using a 5:95 to1:9 gradient to give 121 mg (51% yield) of methyl3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,2-dimethylpropanoate.MS found: (M+H)⁺=341.

(g) Methyl3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,2-dimethylpropanoate(121 mg, 0.355 mmol) was heated to 100 C overnight in a mixture of 2 MNaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidifiedto pH 5 with HCl and extracted 2×EtOAc. The organic layers were washedwith water×2, dried over MgSO₄, filtered, and concentrated in vacuo togive 90 mg (80% yield) of acid3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,2-dimethylpropanoicacid. MS found: (M+H)⁺=327.

h) Example 105 was prepared from3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,2-dimethylpropanoicacid (45 mg, 0.138 mmol) and 1,3,4-thiadiazol-2-amine using GeneralCoupling Method A to give 21 mg (38% yield). MS found: (M+H)⁺=410.

Example 1063-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-methyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(a)(b) 1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-ol [(484 mg, 2.0 mmol;prepared as described in Example 105(c)] was dissolved in DCM (20 mL)and pyridine was added (0.16 mL, 2 mmol) followed by triflic anhydride(0.36 mL, 2.1 mmol). After 1 h, the reaction was washed with 1 M HCl andthe aqueous layer was dried over MgSO₄, filtered, and concentrated. Thecrude1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yltrifluoromethanesulfonate wastaken up in 20 mL DMF, transferred to a stainless steel pressure bomb,and treated with ethyl acrylate (200 mg, 2 mmol), triethylamine (0.28mL, 2 mmol), and Pd(PPh₃)₂Cl₂ (160 mg, 0.2 mmol) and heated at 110° C.for 6 h. The reaction was incomplete so additional ethyl acrylate (200mg, 2 mmol) and Pd(PPh₃)₂Cl₂ (160 mg, 0.2 mmol) was added and thereaction was sealed and heated for 16 h. The reaction was cooled,diluted with EtOAc, washed with brine, and the organic phase was driedover MgSO₄, filtered, and concentrated. The residue was purified by MPLCusing SiO₂ and a 1:9 EtOAc/hexane to 1:1 gradient. Obtained 350 mg (54%yield, 2 steps) of (E)-ethyl3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)acrylate. MS found:(M+H)⁺=325.

(c)(d) (E)-ethyl 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)acrylate(350 mg, 1.08 mmol) was dissolved in EtOH (30 mL) and hydrogenated over10% Pd/C (70 mg) at 50 psi H2 for 4 h. The catalyst was filtered off andthe solution was treated with 1 M NaOH (30 mL) and stirred for 16 h. ThepH was adjusted to 4-5 with conc HCl. Most of the EtOH was removed invacuo and the solution was extracted with EtOAc and dried over MgSO₄,filtered, and conc. Obtained 320 mg (100%) of3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)propanoic acid.

(e) 3-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)propanoic acid [180mg, 0.6 mmol, prepared as described in Example 93(d)] was esterified bydissolving in MeOH and bubbling HCl gas through it. The reaction wasconcentrated in vacuo, extracted with EtOAc and NaHCO₃, and dried overMgSO₄. After filtration and concentration, the ester was dissolved in 5mL dry THF followed by 2 mL potassium hexamethyldisilazane (2 mL of 0.5M toluene solution). After 30 m, iodomethane (168 mg, 1.18 mmol) wasadded and the reaction was stirred for 14 h. The reaction was incompleteso additional KHMDS (2 mL) and iodomethane were added (168 mg). Afteranother 14 h, the reaction was quenched with MeOH followed by extractiveworkup with brine and EtOAc. The crude product was purified by SiO₂chromatography to give 29 mg of3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-methyl-N-(1,3,4-thiadiazol-2-yl)propanamide.MS found: (M+H)⁺=327.

(f)3-(1-(4-Fluorophenyl)-6-methyl-1H-indazol-5-yl)-2-methyl-N-(1,3,4-thiadiazol-2-yl)propanamide(29 mg, 0.07 mmol) was dissolved in 5 mL MeOH followed by 2 mL of 1 MNaOH. The reaction was stirred for 14 h. The reaction was worked up byextraction from KH₂PO₄ with EtOAc and concentrated in vacuo. Theresulting carboxylic acid was coupled to 2-amino-1,2,4-thiadiazole usingGeneral Coupling Method A. The product was purified by HPLC to give thedesired product Example 106. MS found: (M+H)⁺=396. NMR(CDCl₃) δ 8.77 (s,1H); 8.01 (s, 1H) 7.60-7.65 (m, 2H); 7.55 (s, 1H); 7.40 (s, 1H); 7.22(t, 2H); 3.16-3.25 (m, 2H), 2.94-2.95 (m, 1H); 2.48 (s, 3H); 1.37-1.39(dd, 3H).

Example 1073-(1H-Indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide

(a) To a stirred solution of 1H-indole-5-carbaldehyde (0.87 g, 6 mmol)in anhydrous DMF (10 mL) was added sodium hydride (60% dispersion inmineral oil, 0.36 g, 9 mmol) portionwise at 0° C. under argon. Thereaction mixture was stirred at 0° C. for 10 min and rt for 20 minbefore dimethylcarbamic chloride was added dropwise at 0° C. After thereaction mixture was stirred at 0° C. for 10 min and rt for 2 hr,saturated ammonium chloride aqueous solution (10 mL) was added to quenchthe reaction. The reaction mixture was concentrated, diluted with water(10 mL) and extracted with dichloromethane (20 mL). The dichloromethaneextract was dried (Na₂SO₄) and concentrated. Silica gel flashchromatography gave 5-formyl-N,N-dimethyl-1H-indole-1-carboxamide (1.3g, 5.8 mmol, 97% yield) as a white solid, the NMR spectrum of which wasconsistent with the desired structure.

(b) To a stirred solution of5-formyl-N,N-dimethyl-1H-indole-1-carboxamide (0.63 g, 2.9 mmol) inanhydrous THF (5 mL) was added phenyl magnesium bromide solution (3 M indiethyl ether, 1.1 mL, 3.3 mmol) at −78° C. under argon. The reactionmixture was stirred at −78° C. for 1 hr, at rt for 1 hr and quenched bythe slow addition of saturated aq ammonium chloride aqueous solution (10mL) Water (10 mL) was added, the reaction mixture was extracted withethyl acetate (20 mL) dried (Na₂SO₄), filtered through a pad of silicagel, and concentrated to give5-(hydroxy(phenyl)methyl)-N,N-dimethyl-1H-indole-1-carboxamide (0.9 g, 3mmol, 100% yield) as a syrup, the NMR spectrum of which was consistentwith the desired structure.

(c) To a stirred solution of5-(hydroxy(phenyl)methyl)-N,N-dimethyl-1H-indole-1-carboxamide (0.72 g,2.5 mmol) and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (8 mL)in anhydrous dichloromethane (6 mL) was added boron trifluoride diethylether complex (0.83 mL, 6.6 mmol) dropwise at 0° C. under argon. Afterstirring at 0° C. for 30 min and rt for 3.5 hr, the mixture was pouredinto a saturated aqueous sodium bicarbonate solution maintained at 0° C.The reaction mixture was stirred well, extracted with ethyl acetate (20mL), dried (Na₂SO₄) and concentrated. Silica gel flash chromatographygave methyl3-(1-(dimethylcarbamoyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoate(0.9 g, 2.4 mmol, 96% yield) as a glassy solid, the NMR spectrum ofwhich was consistent with the desired structure.

(d) A mixture of methyl3-(1-(dimethylcarbamoyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoate(0.7 g, 2.2 mmol), sodium hydroxide (1M aqueous solution, 18 mL),methanol (5 mL), and dimethylsulfoxide (3 mL) was stirred at 100° C.overnight under argon. The reaction mixture was cooled, washed withdiethyl ether (20 mL), acidified with 6M hydrochloric acid aqueoussolution, and extracted with ethyl acetate (20 mL). The ethyl acetateextract was washed with brine (20 mL), dried (Na₂SO₄) and concentratedto give 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (0.58 g,2.0 mmol, 91% yield) as a syrup and used as such for the subsequent stepwithout further purification.

(e) To a stirred solution of3-(1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (0.31 g, 1.1mmol), 2-aminothiazole (0.2 g, 2 mmol), and diisopropylethylamine (0.5mL) in anhydrous DMF (3 mL) was added HATU (1 g, 2.7 mmol) under argon.After the reaction mixture was stirred at rt for 14 hr and 80° C. for 6hr, it was concentrated, dissolved in ethyl acetate (20 mL), washed withsaturated aqueous sodium bicarbonate solution (10 mL), brine (10 mL),dried (Na₂SO₄), and concentrated. Silica gel flash chromatography gave3-(1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide(Example 107, 0.3 g, 0.8 mmol, 75% yield) as a yellow solid. MS found:(M+H)⁺=376. ¹H-NMR (400 MHz, MeOD) δ ppm 7.60 (1H, s) 7.43 (2H, d,J=7.12 Hz) 7.38 (1H, d, J=3.56 Hz) 7.20-7.29 (3H, m) 7.12-7.20 (2H, m)7.10 (1H, d) 7.04 (1H, d, J=3.56 Hz) 6.38 (1H, d, J=3.05 Hz) 4.70 (1H,s) 4.62 (1H, s) 1.43 (6H, d, J=4.07 Hz).

Example 107 was resolved into its enantiomers using a Chiralpak-ADcolumn and a solvent system of CO₂/MeOH. The enantiomer that elutesfirst has a retention time of 9.19 min. The second enantiomer has aretention time of 13.23 min. There are numerous alternative ways ofresolving compounds of the present invention.

Example 1083-(3-Cyano-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide

To a stirred solution of3-(1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide(Example 101, 25 mg, 0.067 mmol) in anhydrous acetonitrile (1 mL) wasadded chlorosulfonyl isocyanate (0.007 mL, 0.074 mmol) at 0° C. underargon. The reaction mixture was stirred at 0° C. for 30 min beforeanhydrous DMF (0.006 mL, 0.074 mmol) was added. After the reactionmixture was stirred at 0° C. for 30 min and at rt for 1 hr, it wasconcentrated, mixed with saturated aqueous sodium bicarbonate solution(5 mL), and extracted with dichloromethane (10 mL). The dichloromethaneextract was dried (Na₂SO₄) and concentrated. Silica gel flashchromatography gave3-(3-cyano-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide(Example 108, 11 mg, 0.027 mmol, 41% yield) as a white solid. MS found:(M+H)⁺=401. ¹H-NMR (400 MHz, Acetone-d6): δ ppm 11.15 (1H, s) 10.48 (1H,s) 8.06 (1H, d, J=2.40 Hz) 7.78 (1H, s) 7.46-7.53 (3H, m) 7.39 (1H, d,J=8.65 Hz) 7.35 (1H, d, J=3.56 Hz) 7.28 (2H, t, J=7.38 Hz) 7.18 (1H, t,J=7.38 Hz) 7.04 (1H, d, J=3.56 Hz) 5.04 (1H, s) 1.51 (6H, d, J=2.54 Hz).

Example 1093-(3-Formyl-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide

Phosphorus oxychloride (0.01 mL, 0.11 mmol) was added to anhydrous DMF(0.5 mL) under argon. The mixture was stirred at rt for 15 min before3-(1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide(Example 101, 18 mg, 0.048 mmol) was added. The reaction mixture wasstirred at rt for 1 hr. Aqueous sodium hydroxide solution (1N, 2 mL) wasadded, the mixture was stirred at 80° C. for 8 min. The reaction mixturewas quenched with saturated aqueous ammonium chloride solution (1 mL)and water (1 mL) and extracted with dichloromethane (10 mL). Thedichloromethane extract was dried (Na₂SO₄) and concentrated. Silica gelflash chromatography gave3-(3-formyl-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide(Example 109, 16 mg, 0.04 mmol, 83% yield) as a glassy solid. MS found:(M+H)⁺=404. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.93-9.95 (1H, s) 9.92 (1H, s)9.25 (1H, s) 8.34 (1H, s) 7.66 (1H, d, J=3.05 Hz) 7.34-7.39 (3H, m)7.12-7.28 (5H, m) 6.92 (1H, d, J=3.56 Hz) 4.51 (1H, s) 1.42 (6H, s).

Example 1103-(1-(4-Fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide

(a) A mixture of 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid(Example 101(d), 31 mg, 0.11 mmol), 1-bromo-4-fluorobenzene (0.014 mL,0.13 mmol), copper(I) iodide (4 mg, 0.02 mmol), potassium carbonate (50mg, 0.36 mmol), trans-1,2-diaminocyclohexane (0.01 mL, 0.08 mmol),tetrabutylammonium iodide (18 mg, 0.05 mmol), and dioxane (0.6 mL) wasstirred at 110° C. for 24 h. Concentration and purification usingreverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH:90% H₂O: 0.1% TFA, solvent B: 90% MeOH, 10% H₂O, 0.1% TFA) gave3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid(24 mg, 0.062 mmol, 56% yield) as a liquid.

(b) To a stirred solution of3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid(23 mg, 0.059 mmol), 2-aminothiazole (18 mg, 0.18 mmol), anddiisopropylethylamine (0.03 mL, 0.18 mmol) in anhydrous DMF (0.3 mL) wasadded HATU (68 mg, 0.18 mmol) under argon. The reaction mixture wasstirred at rt for 5 min and at 80° C. for 5 hr. Concentration andpurification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run,solvent A: 10% MeOH: 90% H₂O: 0.1% TFA, solvent B: 90% MeOH, 10% H₂O,0.1% TFA) gave3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide(Example 110, 6 mg, 0.013 mmol, 22% yield) as a pink solid. MS found:(M+H)⁺=470. ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.67 (1H, s) 7.32-7.43 (5H, m)7.33 (1H, d, J=8.65 Hz) 7.22-7.28 (3H, m) 7.14-7.20 (4H, m) 6.94 (1H, d,J=3.56 Hz) 6.60 (1H, d, J=3.05 Hz) 4.59 (1H, s) 1.46 (6H, d, J=2.54 Hz).

Example 1112,2-Dimethyl-3-phenyl-3-(2-(pyridin-2-yl)-1H-indol-5-yl)-N-(thiazol-2-yl)propanamide

(a) Methyl 3-(4-bromophenyl)-2,2-dimethyl-3-phenylpropanoate wasprepared from (4-bromophenyl)(phenyl)methanol using the procedureoutlined for Example 107.

(b) A mixture of methyl3-(4-bromophenyl)-2,2-dimethyl-3-phenylpropanoate (1.1 g, 3.0 mmol),benzophenone hydrazone (0.70 g, 3.6 mmol), cesium carbonate (1.5 g, 4.5mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (50 mg, 0.068 mmol), and toluene (3 mL) wasstirred at 95° C. under argon for 12 hr. The reaction mixture was cooledto rt, partitioned between water (10 mL) and ethyl acetate (20 mL),dried (Na₂SO₄), concentrated and purified by silica gel flashchromatography to give the desired product (1.4 g, 3.0 mmol, 100%yield), the NMR spectrum of which was consistent with the desiredstructure.

(c) A mixture of the above coupling product (46 mg, 0.099 mmol),2-acetylpyridine (0.017 mL, 0.15 mmol), p-toluenesulfonic acidmonohydrate (120 mg), ethanol (0.2 mL), and toluene (1 mL) was stirredat 110° C. for 5 hr under nitrogen. A stream of nitrogen gas was thenpassed through the reaction mixture to remove ethanol. The reactionmixture was stirred at 110° C. for an additional 10 hr. Concentrationand purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min.run, solvent A: 10% MeOH: 90% H₂O: 0.1% TFA, solvent B: 90% MeOH, 10%H₂O, 0.1% TFA) gave methyl2,2-dimethyl-3-phenyl-3-(2-(pyridin-2-yl)-1H-indol-5-yl)propanoate (25mg, 0.065 mmol, 66% yield).

(d) Methyl2,2-dimethyl-3-phenyl-3-(2-(pyridin-2-yl)-1H-indol-5-yl)propanoate wasconverted to2,2-dimethyl-3-phenyl-3-(2-(pyridin-2-yl)-1H-indol-5-yl)-N-(thiazol-2-yl)propanamide(Example 111) as a TFA salt using standard HATU coupling method known toone skilled in the art. MS found: (M+H)⁺=453. ¹H-NMR (400 MHz, MeOD) δppm 8.52 (1H, d, J=5.60 Hz) 8.10 (1H, t, J=7.63 Hz) 8.00 (1H, d, J=12Hz) 7.60 (1H, s) 7.44 (1H, t, J=8 Hz) 7.33 (2H, d, J=7.63 Hz) 7.24-7.28(2H, m) 7.12-7.18 (4H, m) 7.07 (1H, t, J=7.38 Hz) 6.93 (1H, d, J=3.56Hz) 4.63 (1H, s) 1.33 (6H, d, J=4.07 Hz).

Example 1122,2-Dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)-N-(thiazol-2-yl)propanamide

(a) To a stirred mixture of (2-amino-4-bromophenyl)(phenyl)methanone(1.0 g, 3.6 mmol) in hydrochloric acid (6N aqueous solution, 5 mL) wasadded sodium nitrite (0.5 g, 7.2 mmol) over 3 min at 0° C. The mixturewas stirred at 0° C. for 30 min before a solution of tin(II) chloride(2.7 g, 14.4 mmol in 5 mL concentrated hydrochloric acid) was added at0° C. over 5 min. After stirring at 0° C. for 10 min and rt for 1 hr,the reaction mixture was filtered. The solid was washed with water (10mL), 4N aqueous sodium hydroxide solution, and water (10 mL). The solidwas dissolved in dichloromethane (20 mL), washed with brine (10 mL),dried (Na₂SO₄), and concentrated. Silica gel flash chromatography gave6-bromo-3-phenyl-1H-indazole (0.42 g, 1.5 mmol, 42% yield).

(b) To a stirred solution of 6-bromo-3-phenyl-1H-indazole (109 mg, 0.40mmol) in anhydrous THF (3 mL) was added n-butyl lithium solution (2M inhexanes, 0.47 mL, 0.94 mmol) dropwise at −78° C. under argon. Thereaction mixture was stirred at −78° C. for 30 min and at −40° C. for 6min before benzaldehyde (0.1 mL, 1 mmol) was added at −40° C. Thereaction mixture was then stirred at rt for 1 hr. quenched withsaturated aqueous ammonium chloride solution (5 mL) and extracted withethyl acetate (10 mL). The ethyl acetate extract was dried (Na₂SO₄) andconcentrated. Silica gel flash chromatography gavephenyl(3-phenyl-1H-indazol-6-yl)methanol (71 mg, 0.24 mmol, 59% yield)as a solid.

(c) To a stirred solution of phenyl(3-phenyl-1H-indazol-6-yl)methanol(67 mg, 0.22 mmol) and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane(2 mL) in anhydrous dichloromethane (4 mL) was added boron trifluoridediethyl ether complex (0.2 mL, 1.6 mmol) dropwise at 0° C. under argon.After stirred at 0° C. for 15 min, rt for 2 hr, and 40° C. for 1.5 hr,the mixture was poured into saturated aqueous sodium bicarbonatesolution at 0° C. The mixture was stirred well and extracted withdichloromethane (10 mL). The dichloromethane layer was dried (Na₂SO₄)and concentrated. Silica gel flash chromatography gave methyl2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoate (45 mg,0.12 mmol, 53% yield) as a glassy solid.

(d) A mixture of methyl2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoate (45 mg,0.12 mmol), lithium hydroxide monohydrate (50 mg, 1.2 mmol), water (2mL), and dioxane (4 mL) was stirred at 110° C. overnight. The mixturewas cooled to rt and partitioned between water (5 mL) and diethyl ether(10 mL). The ether layer was extracted with water (10 mL). The combinedaqueous solutions were acidified with 6N hydrochloric acid, extractedwith ethyl acetate (15 mL), washed with brine (10 mL), dried (Na₂SO₄)and concentrated to give2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoic acid (46 mg,0.12 mmol, 100% yield) as a glassy solid.

(e) To a stirred solution of2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoic acid (26 mg,0.07 mmol), 2-aminothiazole (28 mg, 0.28 mmol), anddiisopropylethylamine (0.05 mL) in anhydrous DMF (0.2 mL) was added HATU(106 mg, 0.28 mmol) under argon. After stirring at rt for 2.5 hr and 80°C. for 1 hr, the mixture was concentrated. Purification using reversephase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H₂O:0.1% TFA, solvent B: 90% MeOH, 10% H₂O, 0.1% TFA) gave2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)-N-(thiazol-2-yl)propanamide(Example 112, 9 mg, 0.02 mmol, 28% yield) as a solid. MS found:(M+H)⁺=453. ¹H-NMR (500 MHz, CDCl₃) δ ppm 7.96 (1H, d, J=8.25 Hz) 7.86(2H, d, J=8.25 Hz) 7.50 (1H, d, J=8.25 Hz) 7.46 (2H, d, J=8.25 Hz)7.39-7.43 (2H, m) 7.35 (2H, d, J=7.70 Hz) 7.17-7.26 (4H, m), 6.96 (1H,d, J=3.30 Hz) 4.62 (1H, s) 1.45 (6H, d, J=3.85 Hz).

Example 1133-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethyl-N-(thiazol-2-yl)butanamide

(a) To a stirred solution of(1-(4-fluorophenyl)-1H-indazol-5-yl)methanol (0.45 g, 1.9 mmol) inacetone (10 mL) was added Jones's reagent (3 mL) dropwise at 0° C. Thereaction mixture was stirred at rt for 1 hr and concentrated underreduced pressure. Water was added to the residue and the solid thatseparates out was filtered, washed with water and dried to give1-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.43 g, 1.7 mmol, 89%yield) as a yellow solid.

(b) To a stirred suspension of the1-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.22 g, 0.81 mmol) inmethanol (5 mL), THF (5 mL), and dichloromethane (5 mL) was added(trimethylsilyl)diazomethane solution (2M in diethyl ether, 1 mL, 2mmol) dropwise at rt. The reaction mixture was stirred at rt for 1 hrand carefully quenched by the slow addition of acetic acid.Concentration under reduced pressure and titration with methanol gavemethyl 1-(4-fluorophenyl)-1H-indazole-5-carboxylate (0.16 g, 0.59 mmol,73% yield) as a white solid.

(c) To a suspension of methyl1-(4-fluorophenyl)-1H-indazole-5-carboxylate (84 mg, 0.31 mmol) inanhydrous THF (5 mL) was added methylmagnesium bromide (3M solution indiethyl ether, 1 mL, 3 mmol) dropwise at rt under argon. The reactionmixture was stirred at rt for 1 hr and carefully quenched by the slowaddition of saturated aqueous ammonium chloride solution (10 mL). Thereaction mixture was extracted with ethyl acetate (10 mL), dried(Na₂SO₄), concentrated and purified by silica gel flash chromatographyto give 2-(1-(4-fluorophenyl)-1H-indazol-5-yl)propan-2-ol (84 mg, 0.31mmol, 100% yield) as a syrup.

(d) To a stirred solution of2-(1-(4-fluorophenyl)-1H-indazol-5-yl)propan-2-ol (82 mg, 0.30 mmol) and(1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.5 mL) in anhydrousdichloromethane (3 mL) was added titanium(IV) tetrachloride (1M solutionin toluene, 1.2 mL, 1.2 mmol) dropwise at 0° C. under argon. Thereaction mixture was stirred at 0° C. for 1 hr and rt for 1 hr beforebeing quenched by the slow addition of saturated aqueous sodiumbicarbonate solution. The reaction mixture was filtered through a pad ofcelite that was then washed with ethyl acetate (10 mL). The ethylacetate layer was separated and the aqueous layer was reextracted withethyl acetate (10 mL). The combined ethyl acetate layers were dried(Na₂SO₄), concentrated and purified by silica gel flash chromatographyto give methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutanoate (100 mg,0.28 mmol, 94% yield) as a white solid.

(e) A mixture of methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutanoate (63 mg,0.18 mmol), lithium iodide (120 mg, 0.9 mmol), sodium cyanide (45 mg,0.9 mmol), and pyridine (1 mL) was heated in CEM Explorer microwavereactor under nitrogen at 150° C. for 30 min and 160° C. for 1 hr. Thereaction mixture was concentrated and diluted with ethyl acetate (5 mL)and saturated aqueous sodium bicarbonate solution. The solid3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutanoic acid (46mg) that separates out was filtered, washed with water, dried and usedas such for the subsequent step without further purification.

(f) (23 mg; 0.06 mmol) of the above solid, 1-hydroxy-7-azabenzotriazole(14 mg, 0.1 mmol), DMF (0.3 mL), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (37 mg,0.19 mml) was stirred at rt for 20 min before 2-aminothiazole (32 mg,0.32 mmol) was added. The reaction mixture was heated in a CEM Explorermicrowave reactor under nitrogen at 130° C. for 30 min. Purificationusing reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10%MeOH: 90% H₂O: 0.1% TFA, solvent B: 90% MeOH, 10% H₂O, 0.1% TFA) gave3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethyl-N-(thiazol-2-yl)butanamide(Example 113, 8 mg, 0.019 mmol, 21% yield from the ester) as a whitesolid. MS found: (M+H)⁺=423. ¹H-NMR (400 MHz, Acetone-d6): δ ppm 10.01(1H, s) 8.07 (1H, s) 7.77 (1H, s) 7.64-7.70 (2H, m) 7.50 (1H, d, J=9.16Hz) 7.36-7.41 (1H, m) 7.29 (1H, d, J=3.56 Hz) 7.21-7.27 (2H, m) 7.04(1H, d J=4.07 Hz) 1.49 (6H, s) 1.24 (6H, s).

Example 1143-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-methyl-N-(thiazol-2-yl)butanamide

(a) To a stirred solution of2-(1-(4-fluorophenyl)-1H-indazol-5-yl)propan-2-ol (Example 113(d), 200mg, 0.74 mmol) and trimethyl(vinyloxy)silane (0.5 mL) in anhydrousdichloromethane (1 mL) was added zinc chloride (1M solution in diethylether, 2.2 mL, 2.2 mmol) dropwise at 0° C. under argon. The reactionmixture was stirred at rt for 1.5 hr before being quenched by theaddition of saturated aqueous ammonium chloride solution (2 mL). Theaqueous layer was separated and extracted with ethyl acetate (2×2 mL).The combined organic layers were dried (Na₂SO₄), concentrated andpurified by silica gel flash chromatography to give3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanal as a liquid.

(b) To a stirred solution of the above3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanal in acetone (3 mL)was added Jones' reagent (1 mL) dropwise at 0° C. The reaction mixturewas stirred at 0° C. for 30 min before being concentrated under reducedpressure. The residue was neutralized with saturated aqueous sodiumbicarbonate solution and 10% aqueous citric acid solution, and thenextracted with ethyl acetate (3×10 mL). The combined ethyl acetateextracts were dried (Na₂SO₄), concentrated and purified by reverse phaseHPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H₂O: 0.1%TFA, solvent B: 90% MeOH, 10% H₂O, 0.1% TFA) to give3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanoic acid (100 mg,0.32 mmol, 43% yield for 2 steps) as a yellow oil.

(c) To a stirred solution of3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanoic acid (14 mg,0.045 mmol) and diisopropylethylamine (0.05 mL) in anhydrous DMF (0.3mL) was added HATU (30 mg, 0.079 mmol) at 0° C. under argon. Afterstirring at 0° C. for 5 min, 2-aminothiazole (15 mg, 0.15 mmol) wasadded. The reaction mixture was stirred at rt for 5 min and 50° C. for30 min. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min.run, solvent A: 10% MeOH: 90% H₂O: 0.1% TFA, solvent B: 90% MeOH, 10%H₂O, 0.1% TFA) gave3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methyl-N-(thiazol-2-yl)butanamide(Example 114, 9 mg, 0.02 mmol, 44% yield) as a white solid. MS found:(M+H)⁺=395. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.04 (1H, s) 7.67 (1H, s) 7.58(2H, dd, J=8.90, 4.83 Hz) 7.53 (1H, d, J=9.16 Hz) 7.40-7.46 (1H, m) 7.25(1H, s) 7.14 (2H, t, J=8.65 Hz) 6.87 (1H, s) 2.81 (2H, s) 1.51 (6H, s).

Examples 115 to 135

Compounds listed in the table below were prepared using methodsdescribed in Examples 107 to 114.

LC Procedure Retention Ex. Name Product Structure of Example [M + H]⁺Time (min)* 115 2,2-dimethyl-3-phenyl-3- (2-(pyridin-4-yl)-1H-indol-5-yl)-N-(thiazol-2- yl)propanamide

100 453 2.83 116 2,2-dimethyl-3-phenyl-3- (2-(pyridin-4-yl)-1H-indol-5-yl)-N-(1,3,4- thiadiazol-2- yl)propanamide

100 454 2.69 117 2,2-dimethyl-3-phenyl- N-(thiazol-2-yl)-3-(2-(thiazol-2-yl)-1H-indol- 5-yl)propanamide

100 459 3.67 118 2,2-dimethyl-3-phenyl- N-(1,3,4-thiadiazol-2-yl)-3-(2-(thiazol-2-yl)-1H- indol-5-yl)propanamide

100 460 3.56 119 2,2-dimethyl-3-phenyl- N-(thiazol-2-yl)-3-(2-p-tolyl-1H-indol-5- yl)propanamide

100 466 4.06 120 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-2,2,3-trimethyl-N-(1,3,4- thiadiazol-2- yl)butanamide

103 424 3.81 121 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-N-(2-hydroxycyclopentyl)- 2,2,3- trimethylbutanamide

103 424 3.71 122 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-3-methyl-N-(1,3,4- thiadiazol-2- yl)butanamide

104 396 3.48 123 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-2,2-dimethyl-4-phenyl-N- (1,3,4-thiadiazol-2- yl)butanamide

105 486 3.80 124 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-N- ((1S,2S)-2-hydroxycyclopentyl)-2,2- dimethyl-4- phenylbutanamide

105 86 3.71 125 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-N-(2-hydroxycyclopentyl)-2,2- dimethyl-4-p- tolylbutanamide

105 500 3.88 126 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-2,2-dimethyl-N-(thiazol-2- yl)-4-p-tolylbutanamide

105 499 4.10 127 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4- thiadiazol-2-yl)-4-p- tolylbutanamide

105 500 3.98 128 N-cyclopropyl-3-(1-(4- fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-4- phenylbutanamide

105 442 3.71 129 N-cyclobutyl-3-(1-(4- fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-4- phenylbutanamide

105 456 3.85 130 N-cyclopentyl-3-(1-(4- fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-4- phenylbutanamide enantiomer 1

105 470 3.96 131 N-cyclopentyl-3-(1-(4- fluorophenyl)-1H-indazol-5-yl)-2,2- dimethyl-4- phenylbutanamide enantiomer 2

105 470 3.96 132 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-2,2-dimethyl-4-phenyl-N- (tetrahydro-2H-pyran-4- yl)butanamide

105 486 3.71 133 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-2,2-dimethyl-4-phenyl-N- (piperidin-4- yl)butanamide

105 485 3.10 134 3-(1-(4-fluorophenyl)- 1H-indazol-5-yl)-N-(3-hydroxy-2,2- dimethylpropyl)-2,2- dimethyl-4- phenylbutanamide

105 488 3.53 135 (S)-3-(1-(4- fluorophenyl)-1H- indazol-5-yl)-N-(2-hydroxycyclopentyl)-2,2- dimethyl-3- phenylpropanamide

113 472 3.69

Example 1363-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(a) (1-(4-Fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (Example 1(f))(2.4 g, 7.54 mmol) was dissolved in 50 mL of DCM and treated with DessMartin periodinane (3.2 g, 7.54 mmol) and stirred overnight. The nextday, the reaction was extracted from 2 M NaOH with DCM (vigorousshaking)×3, dried over MgSO4, filtered, and concentrated in vacuo. Thecrude material was filtered through a silica gel pad using EtOAc andconcentrated to give(1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanone (2.4 g, 100%). MSfound: (M+H)⁺=317.

(b) Trimethylphosphonoacetate (2.4 g, 13.4 mmol) was dissolved in 15 mLanhydrous DMF and treated with sodium hexadimethylsilazane (13.4 mmol, 1M in THF). (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanone (1.63g, 5.16 mmol) was added and the reaction was heated to 85° C. for 16hours. The following day, the cooled reaction was extracted from brineusing ether×3 and the combined organic layers were dried over MgSO4,filtered, and concentrated in vacuo. The residue was chromatographed onsilica gel using 25% EtOAc in hexanes to give 1.74 g (91%) of (E)-methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylacrylate as a clear oil.MS found: (M+H)⁺=373.

(c) (E)-methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylacrylatewas dissolved in 30 mL EtOH in a Parr bottle and flushed with N2. 10% Pdon carbon was added and the reaction was put on a Parr shaker under 50psi of H2 for 7 hours. LC-MS after this time indicated that the reactionwas complete so the catalyst was filtered off and the solutionconcentrated in vacuo. The residue was purified using a 40 g MPLC columnusing a 10 to 25% EtOAc in hexanes gradient to give methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoate (1.1 g, 64%).MS found: (M+H)⁺=375.

(d) Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoate(700 mg, 1.87 mmol) was dissolved in 45 mL MeOH/H₂O (8:1) and treatedwith NaOH (2 M, 10.8 mmol, 5.4 mL). The reaction was complete in 2 hoursand was acidified with 1 M HCl and extracted 3×EtOAc, the combinedorganic layers were dried over MgSO4, filtered, and concentrated invacuo to give pure3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoic acid (620 mg,92%) as a clear oil. MS found: (M+H)⁺=361

(e) Example 136 was prepared from3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoic acid (504 mg,1.4 mmol) and 2-amino-1,3,4-thiadiazole using General Coupling Method Ato give 310 mg (50% yield). MS found: (M+H)⁺=444. Resolution of thiscompound into its enantiomers could be accomplished using chiral HPLC asdescribed above.

Example 1373-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-N-(1-methyl-1H-1,2,4-triazol-3-yl)-3-phenylpropanamide

Example 137 was prepared from3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoic acid (50 mg,0.14 mmol) and 1-methyl-1H-1,2,4-triazol-3-amine using General CouplingMethod A to give 7 mg (11% yield). MS found: (M+H)⁺=441.5.

Example 1383-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenyl-N-(thiazol-2-yl)butanamide

(a) To 1-(4-fluorophenyl)-1H-indazole-5-carbaldehyde (240 mg, 1.0 mmol)in anhydrous THF (5 mL) was added benzylmagnesium bromide (19% solutionin THF, 3 mL, 3 mmol) dropwise at rt under argon. The reaction mixturewas stirred at rt for 30 min and quenched by the slow addition ofsaturated aqueous ammonium chloride solution (5 mL). The mixture wasextracted with ethyl acetate (2×4 mL). The combined ethyl acetateextracts were dried (Na₂SO₄), concentrated and purified by silica gelflash chromatography to give1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylethanol (330 mg, 1.0mmol, 100% yield) as a yellow oil.

(b) To a stirred solution of1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylethanol (290 mg, 0.87mmol) and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.7 mL, 3.5mmol) in anhydrous dichloromethane (5 mL) was added titanium(IV)tetrachloride (1M solution in toluene, 1.9 mL, 1.9 mmol) dropwise at 0°C. under argon. The reaction mixture was stirred at 0° C. for 30 min andrt for 2 hr before being quenched by the slow addition of saturatedaqueous sodium bicarbonate solution (15 mL). The mixture was filteredthrough a pad of celite that was then washed with dichloromethane (10mL). The aqueous filtrate was reextracted with dichloromethane (10 mL).The combined dichloromethane layers were dried (Na₂SO₄), concentratedand purified by silica gel flash chromatography to give methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoate(216 mg, 0.52 mmol, 60% yield) as an oil.

(c) A mixture of methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoate(210 mg, 0.50 mmol), lithium hydroxide monohydrate (80 mg, 1.9 mmol),water (3 mL), and dioxane (6 mL) was stirred at 90° C. for 24 hr undernitrogen. The reaction mixture was cooled to rt before diethyl ether (20mL) was added. The ether layer was reextracted with water (2×3 mL). Thecombined aqueous solutions were acidified with aqueous 10% citric acidsolution and extracted with ethyl acetate (3×6 mL). The combined ethylacetate extracts were dried (Na₂SO₄) and concentrated to give3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoicacid (200 mg, 0.50 mmol, 100% yield) as a solid.

(d) To a stirred solution of3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoicacid (10 mg, 0.025 mmol) and diisopropylethylamine (0.05 mL) inanhydrous DMF (0.2 mL) was added HATU (25 mg, 0.066 mmol) at rt underargon. After stirring at rt for 10 min, 2-aminothiazole (15 mg, 0.15mmol) was added. The reaction mixture was stirred at rt for 2.5 hr, 40°C. for 1 hr, and 80° C. for 30 min. Purification using reverse phaseHPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H₂O: 0.1%TFA, solvent B: 90% MeOH, 10% H₂O, 0.1% TFA) gave3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenyl-N-(thiazol-2-yl)butanamide(Example 138, 7 mg, 0.01 mmol, 40% yield) as a white solid. MS found:(M+H)⁺=485. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.00 (1H, s) 7.53-7.58 (3H, m)7.44 (1H, d, J=8.65 Hz) 7.35 (1H, d, J=3.56 Hz) 7.23 (1H, d, J=7.63 Hz)7.11-7.15 (2H, m) 6.89-6.99 (7H, m) 3.63(1H, dd, J=10.43, 4.32 Hz)2.97-3.08 (2H, m) 1.37 (3H, s) 1.18 (3H, s).

Example 139(E)-3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethyl-N-(1,3,4-thiadiazol-2-yl)hex-3-enamide

(a) To solution of 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (1.0g, 4.1 mmol) in 10 mL of THF was added 2.0 M isobutylmagnesium bromidein ether. The reaction mixture was stirred 2 h and then quenched withMeOH. Poured into sat. KH₂PO₄ and extracted with EtOAc×3. The organiclayers were dried over MgSO₄, filtered, and concentrated. The residuewas purified by SiO₂ chromatography eluting with 5% EtOAc/DCM. Obtained650 mg (49% yield) of1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol. MS found:(M+H)⁺=299.

(b) 1-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol (650 mg,2.17 mmol) was dissolved in 50 mL dry DCM and Dess-Martin periodinane(1.0 g, 2.36 mmol) was added. The reaction mixture was stirred for 12 h.The reaction was poured into 1N NaOH and extracted with DCM×3. Theorganic layers were dried over MgSO₄, filtered, and concentrated to give600 mg (92% yield) of1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-one. MS found:(M+H)⁺=297.

(c) 1-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-one (220 mg,0.742 mmol) was dissolved in 10 mL of dry DCM and1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.162 mL, 0.8 mmol) wasadded. The reaction mixture was cooled to 0° C. and TiCl₄ (0.8 mL of 1.0M DCM solution, 0.8 mmol) was added portionwise and then stirred 12 h.The reaction was quenched with aqueous sodium bicarbonate and extracted2×DCM. The organic layers were dried over MgSO₄, filtered, andconcentrated. The residue was purified SiO₂ chromatography eluting with1:1 EtOAc/hexane to give 280 mg (95% yield) of methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2,5-trimethylhexanoate.MS found: (M+H)⁺=399.

(d) Methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2,5-trimethylhexanoate(280 mg, 0.7 mmol) was dissolved in 10 mL MeOH and 5 mL H₂SO₄ and heatedat 90° C. for 12 h. After 12 h, diluted with water and extracted withEtOAc×3. The organic layers were dried over MgSO₄, filtered, andconcentrated. The residue was purified by SiO₂ chromatography elutingwith 1:9 EtOAc/hexane. Obtained 220 mg (82% yield) of (E)-methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate. MSfound: (M+H)⁺=381.

(e) (E)-Methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate (121mg, 0.29 mmol) was dissolved in MeOH (10 mL) and DMSO (10 mL) andtreated with 1 M NaOH (10 mL) at 100° C. After stirring overnight, theMeOH was removed in vacuo, the residue acidified with sat KH₂PO₄ to pH4-5 and extracted with EtOAc×3. The organic layer was dried with MgSO₄,filtered, concentrated in vacuo to give 200 mg (94% yield) of(E)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoicacid. MS found: (M+H)⁺=367.

(f) Example 139 was prepared from(E)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoicacid (105 mg, 0.29 mmol) and 1,3,4-thiadiazol-2-amine using GeneralCoupling Method B to give 30 mg (25% yield). MS found: (M+H)⁺=450.

Example 1403-(Benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(a) To solution of 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (1.0g, 4.16 mmol) and 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.85mL, 4.2 mmol) in 10 mL of dry DCM at 0° C. was added TiCl₄ (0.8 mL of1.0 M DCM solution, 0.8 mmol) The reaction was stirred 2 h and thenquenched with aqueous sodium bicarbonate and extracted 2×EtOAc. Theorganic layers were dried over MgSO₄, filtered, and concentrated. Theresidue was purified by SiO₂ chromatography eluting with 1:2EtOAc/hexane to give 700 mg (50% yield) of methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2-dimethylpropanoate.MS found: (M+H)⁺=343.

(b) Methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2-dimethylpropanoate(282 mg, 0.82 mmol) was dissolved in 10 mL DCM andbenzyl-2,2,2-trichloroacetimidate (0.185 mL, 1.0 mmol) was addedfollowed by 3 drops of CF₃SO₃H. The reaction was stirred for 2 h.Reaction was incomplete so added more benzyl-2,2,2-trichloroacetimidate(0.185 mL, 1.0 mmol). After 12 h, diluted with brine and extracted withDCM×3. The organic layers were dried over MgSO₄, filtered, andconcentrated. The residue was purified by SiO₂ chromatography elutingwith EtOAc/hexane gradient. Obtained 52 mg (15% yield) of methyl3-(benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate.MS found: (M+H)⁺=433.

(c) (E)-Methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate (52mg, 0.123 mmol) was dissolved in MeOH (5 mL) and DMSO (5 mL) and treatedwith 1 M NaOH (5 mL) at 100° C. After stirring overnight, the MeOH wasremoved in vacuo, the residue acidified with sat KH₂PO₄ to pH 4-5 andextracted with EtOAc×3. The organic layer was dried with MgSO₄,filtered, concentrated in vacuo to give3-(benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoicacid.

(d) Example 140 was prepared from3-(benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoicacid and 1,3,4-thiadiazol-2-amine using General Coupling Method A togive 8 mg (13% yield). MS found: (M+H)⁺=502. NMR(CDCl₃) δ 8.20 (s, 1H);7.60-7.76 (m, 4H) 7.2-7.4 (m, 9H); 4.63-4.66 (d, 1H); 4.60 (s, 1H);4.20-4.23 (d, 1H); 1.30 (s, 3H); 1.22 (s, 3H).

General Silyl Ketene Acetal Method A

To a solution of LDA (1 eq) in THF (10-20 mL) at −78° C. was added ester(12-36 mmol). After stirring for 1 h, TMS-Cl (2 eq.) was added and thereaction is allowed to gradually warm to 25° C. The reaction mixture wasfiltered through a sintered glass funnel and filtrate was concentratedin vacuo. The residue was triturated in hexanes and solid were againfiltered away. Filtrate was concentrated in vacuo and used in the nextstep.

General Silyl Ketene Acetal Method B

To a carboxylic acid chloride or acid fluoride (e.g., 6-50 mmol) wasadded benzyl alcohol (1 eq.). The reaction was stirred for 2 hr, thenquenched with 1N NaOH and extracted with 2×EtOAc. The EtOAc extractswere dried over MgSO₄, filtered, and concentrated by rotary evaporatorto give the corresponding benzyl ester. To a solution of LDA (1 eq) inTHF (10-20 mL) at −78° C. was added benzyl ester (12-36 mmol). Afterstirring for 1 h, TMS-Cl (2 eq.) was added and the reaction is allowedto gradually warm to 25° C. The reaction mixture was filtered through asintered glass funnel and filtrate was concentrated in vacuo. Theresidue was triturated in hexanes and solid were again filtered away.Filtrate was concentrated in vacuo and used in the next step.

The procedure of Scheme Y was used in preparing Examples 141 to 150.

Example 1413-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(a)(b) To a solution of(1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (800 mg, 2.5 mmol)and (1-methoxyprop-1-enyloxy)trimethylsilane (1 mL, 6.25 mmol) in 30 mLof dry DCM was added TiCl₄ (2.5 mL of 1.0 M DCM solution, 2.5 mmol) andthen stirred 1 h. The reaction was quenched with MeOH, poured intoaqueous sodium bicarbonate and extracted 2×EtOAc. The organic layerswere dried over MgSO₄, filtered, concentrated to give methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoat. Crudemethyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoate washeated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1).The next day, the reaction was cooled, acidified to pH 5 with HCl andextracted 2×EtOAc. The organic layers were washed with water×2, driedover MgSO₄, filtered, concentrated in vacuo, and purified by HPLC togive 770 mg (82% yield, 2 steps) of acid3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid.MS found: (M+H)⁺=375.

c) Example 141 was prepared from3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid(40 mg, 0.26 mmol) and 1,3,4-thiadiazol-2-amine using General CouplingMethod A to give 6 mg (42% yield). MS found: (M+H)⁺=458.

Resolution of this compound into its four diastereomers could beaccomplished using chiral HPLC as described above.

Diastereomer A: NMR(CDCl₃) δ 8.82 (bs, 1H); 8.20 (s, 1H); 7.9 (s, 1H)7.62-7.64 (m, 3H); 7.52 (d, 1H); 7.34 (d, 2H); 7.2-7.3 (m, 3H); 7.12 (t,2H); 7.05 (t, 1H); 4.40-4.42 (d, 1H); 3.89-3.93 (m, 1H); 1.29-1.31 (d,3H).

Diastereomer B: NMR(CDCl₃) δ 8.71 (br s, 1H); 8.05 (s, 1H); 7.77 (s, 1H)7.5-7.6 (m, 2H); 7.4-7.5 (m, 4H); 7.34 (t, 2H); 7.20-7.26 (m, 1H); 7.19(t, 2H); 7.05 (t, 1H); 4.40-4.43(d, 1H); 3.7-3.8 (m, 1H); 1.29-1.31 (d,3H).

Example 1422-((1-(4-Fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-N-(1,3,4-thiadiazol-2-yl)butanamide

(a) To a solution of(1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (250 mg, 0.79 mmol)and ((1-methoxybut-1-enyloxy)trimethylsilane (32 mmol) which wasprepared using General Silyl Ketene Acetal Method A in 10 mL of dry DCMwas added TiCl₄ (0.8 mL of 1.0 M DCM solution, 0.8 mmol) and thenstirred 1 h. The reaction was quenched with MeOH, poured into aqueoussodium bicarbonate and extracted 2×EtOAc. The organic layers were driedover MgSO₄, filtered, concentrated and purified on SiO₂ by MPLC using aEtOAc/hexane gradient to give 200 mg (63% yield) of methyl2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoate. MSfound: (M+H)⁺=403.

(b) Methyl2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoate washeated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1).The next day, the reaction was cooled, acidified to pH 5 with HCl andextracted 2×EtOAc. The organic layers were washed with water×2, driedover MgSO₄, filtered, concentrated in vacuo, and purified by HPLC togive 180 mg (93% yield) of acid2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoic acid. MSfound: (M+H)⁺=389.

c) Example 142 was prepared from2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoic acid (180mg, 0.26 mmol) and 1,3,4-thiadiazol-2-amine using General CouplingMethod B to give 75 mg (35% yield). MS found: (M+H)⁺=472.

Examples 143 to 150

Examples 143 to 150 in the Table below were prepared using the samemethod as used for Examples 139 and 140 using the appropriate silylketene acetal and general silyl keten acetal method shown in the table.

Silyl Ketene Ex. Name Product Structure Acetal/Method (M + H)+ 1432-((1-(4-fluorophenyl)-1H-indazol-5- yl)(phenyl)methyl)-N-(1,3,4-thiadiazol-2-yl)pentanamide

486 144 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-3-methyl-N- (1,3,4-thiadiazol-2-yl)butanamide

486 145 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenyl-N-(1,3,4-thiadiazol- 2-yl)propanamide

520 (1:1 mixture of diastereomers): NMR (CDCl₃) δ 8.94 (s, 0.5 H); 8.91(s, 0.5 H); 8.01 (s, 0.5 H); 7.99 (s, 0.5 H); 7.93 (S, 0.5 H); 7.68 (s,0.5 H); 7.4-7.65 (m, 7 H) 7.30-7.33 (d, 1 H); 7.09-7.20 (m, 7 H); 7.0(t, 1 H); 5.37-5.39 (dd, 1 H); 5.09-5.11 (dd, 1 H); 3.89-3.93 (m, 1 H).146 2-benzyl-3-(1-(4-fluorophenyl)-1H- indazol-5-yl)-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

534 147 2-cyclopentyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenyl-N-(1,3,4- thiadiazol-2-yl)propanamide

512 148 2-cyclohexyl-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenyl-N-(1,3,4- thiadiazol-2-yl)propanamide

525 149 2-ethyl-2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-N- (1,3,4-thiadiazol-2-yl)butanamide

500 150 1-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-N-(1,3,4- thiadiazol-2- yl)cyclohexanecarboxamide

512 NMR (CDCl₃) δ 8.8 (s, 1 H); 8.11 (d, 1 H); 7.85 (s, 1 H) 7.60-7.65(m, 2 H); 7.52-7.55 (d, 1 H); 7.38-7.45 (m, 3 H); 7.15-7.26 (m, 6 H);4.35 (s, 1 H); 2.41-2.44 (m, 2 H); 1.67-1.77 (m ,4 H); 1.1- 1.45 (m, 4H).

Example 1513-(1H-Indazol-5-yl)-2-methyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(a) To a solution of (1H-indazol-5-yl)(phenyl)methanol (180 mg, 0.71mmol) and (1-methoxyprop-1-enyloxy)trimethylsilane (0.32 mL, 1.78 mmol)in 10 mL of dry MeCN was added TiCl₄ (2.5 mL of 1.0 M DCM solution, 2.5mmol) and then stirred 1 h. The reaction was incomplete so added 10 mLof DCM and additional (1-methoxyprop-1-enyloxy)trimethylsilane (0.3 mL,1.7 mmol) After 1 h, the reaction was quenched with MeOH, poured intoaqueous sodium bicarbonate and extracted 2×EtOAc. The organic layerswere dried over MgSO₄, filtered, and concentrated. HPLC purificationresulted in the resolution of the two diastereomers of methyl3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoate which were takenindependently to the next step. MS found: (M+H)⁺=295.

(b) Each diastereomer of methyl3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoate was heated to 100° C.overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, thereaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc.The organic layers were washed with water×2, dried over MgSO₄, filtered,concentrated in vacuo, and purified by HPLC to give 27 mg (82% yield, 2steps) and 35 mg of the diastereomers of acid3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid. MS found:(M+H)⁺=281.

(c) Example 151 was prepared from3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid (40 mg, 0.26 mmol)and 1,3,4-thiadiazol-2-amine using General Coupling Method A to give 6mg (42% yield). MS found: (M+H)⁺=364. 400 MHz ¹H-NMR (CDCl3) δ 8.77 (s,1H); 7.90 (s, 1H); 7.75 (s, 1H); 7.75 (s, 1H); 7.47 (m, 4H); 7.36 (appt, 2H); 7.25 (dd, 2H); 4.35 (d, 1H); 3.87 (m, 1H); 1.31 (d, 3H).

Example 1523-(1H-Indazol-5-yl)-2,3-diphenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(a) To a solution of (1H-indazol-5-yl)(phenyl)methanol (1.1 g, 5.0 mmol)in 50 mL of dry THF was added EtN₃ (2.8 mL, 20 mmol) and aceticanhydride (1.9 mL, 20 mmol). The reaction was heated at reflux for 12 h.The reaction was quenched with aqueous sodium bicarbonate and extracted2×EtOAc. The organic layers were dried over MgSO₄, filtered, andconcentrated. The residue was taken up in toluene and concentrated invacuo×2 to remove any excess acetic anhydride. Obtained a quantitativeyield of (1H-indazol-5-yl)(phenyl)methyl acetate. MS found: (M+H)⁺=309.

(b) To a solution of (1H-indazol-5-yl)(phenyl)methyl acetate (245 mg,0.8 mmol) and (1-methoxy-2-phenylvinyloxy)trimethylsilane (1.78 g, 8.0mmol, prepared using General Silyl Ketene Acetal Method A) in 20 mL ofdry DCM was added TiCl₄ (0.8 mL of 1.0 M DCM solution, 0.8 mmol) andthen stirred 3 h. The reaction was quenched with MeOH, poured intoaqueous sodium bicarbonate and extracted 2×EtOAc. The organic layerswere dried over MgSO₄, filtered, and concentrated. MPLC purificationusing a 0-40% EtOAc/hexane gradient gave 170 mg (60% yield) of methyl3-(1H-indazol-5-yl)-2,3-diphenylpropanoate. MS found: (M+H)⁺=357.

(c) Methyl 3-(1H-indazol-5-yl)-2,3-diphenylpropanoate was heated to 100°C. overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day,the reaction was cooled, acidified to pH 5 with HCl and extracted2×EtOAc. The organic layers were washed with water×2, dried over MgSO₄,filtered, concentrated in vacuo, and purified by HPLC to give 10 mg (82%yield) and 30 mg of the diastereomers of acid3-(1H-indazol-5-yl)-2,3-diphenylpropanoic acid. MS found: (M+H)⁺=343.

(d) Example 152 was prepared from3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid (10 and 30 mg, 0.03and 0.88 mmol) and 1,3,4-thiadiazol-2-amine using General CouplingMethod A to give 4 mg (% yield) and 6 mg of the respectivediastereomers. MS found: (M+H)⁺=426. NMR(CDCl₃) δ 8.8 (s, 1H); 7.97-8.01(d, 1H); 7.60 (s, 1H) 7.0-7.59 (m, 12H); 4.85(d, 1H); 4.56 (d, 1H).

Example 153 Methyl4-(3-(1,3,4-thiadiazol-2-ylamino)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-oxopropyl)benzoate

(a) To solution of 4-bromobenzonitrile (182 mg, 1.0 mmol) in 5 mL of dryTHF at −78° C. was added n-BuLi (0.7 mL of 1.6 M hexanes solution, 1.1mmol). The reaction was stirred 30 min and then1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (240 mg, 1.0 mmol) wasadded and the reaction mixture was allowed to warm to RT. After 12 h,quenched with brine and extracted 2×EtOAc. The organic layers were driedover MgSO₄, filtered, and concentrated. The residue was purified on SiO₂by MPLC eluting with a 0-30% EtOAc/hexane gradient to give 180 mg (52%yield) of4-((1-(4-fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzonitrile. MSfound: (M+H)⁺=344.

(b) 4-((1-(4-Fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzonitrile(180 mg, 0.52 mmol) was dissolved in MeOH (5 mL) and DMSO (5 mL) andtreated with 1 M NaOH (5 mL) at 100° C. After 36 h, the MeOH was removedin vacuo, the residue acidified with sat KH₂PO₄ to pH 4-5 and extractedwith EtOAc×3. The organic layer was dried with MgSO₄, filtered,concentrated in vacuo to give 180 mg (95% yield) of4-((1-(4-fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzoic acid. MSfound: (M+H)⁺=362.

(c) To a solution of4-((1-(4-fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzoic acid (180mg, 0.5 mmol) and (Z)-(1-(benzyloxy)prop-1-enyloxy)trimethylsilane (10.0mmol, prepared using General Silyl Ketene Acetal Method A) in 10 mL ofdry DCM was added TiCl₄ (1.0 mL of 1.0 M DCM solution, 1.0 mmol) andthen stirred 3 h. The reaction was quenched with MeOH, poured intoaqueous sodium bicarbonate and extracted 2×EtOAc. The organic layerswere dried over MgSO₄, filtered, and concentrated. MPLC purification onSiO₂ using a 0-100% EtOAc/hexane gradient gave 140 mg (55% yield) of4-(3-(benzyloxy)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-oxopropyl)benzoicacid. MS found: (M+H)⁺=509.

(d) To a solution of4-(3-(benzyloxy)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-oxopropyl)benzoicacid (135 mg, 0.265 mmol) in 10 mL of dry MeOH was bubbled HCl gas for15 min. After 1 h, most of the MeOH was removed in vacuo, then pouredinto aqueous sodium bicarbonate and extracted 2×EtOAc. The organiclayers were dried over MgSO₄, filtered, and concentrated. Crude productwas taken to the next step.

(e) The crude residue was dissolved in 50 mL of MeOH. 10% Pd/C (60 mg)was added and the reaction mixture was hydrogenated at 50 psi H2 using aParr shaker. After 2 h, removed H2 and filtered away Pd/C. The filtratewas concentrated in vacuo to give3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-(4-(methoxycarbonyl)phenyl)-2-methylpropanoicacid. MS found: (M+H)⁺=433.

(f) Example 153 was prepared from3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-(4-(methoxycarbonyl)phenyl)-2-methylpropanoicacid and 1,3,4-thiadiazol-2-amine using General Coupling Method A togive 35 mg (25% yield, 3 steps). MS found: (M+H)⁺=516.

The procedure of Scheme AC was used to prepare Examples 154 and 155.

Example 1543-(1,3,4-Thiadiazol-2-ylamino)-2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-2-methyl-3-oxopropylacetate

(a) To solution of dimethyl malonate (0.22 mL, 1.65 mmol) in benzene (15mL) and acetic acid (3 drops) was added1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (330 mg, 1.38 mmol). Thereaction mixture was heated at reflux overnight. The reaction wasquenched with sat. KH₂PO₄ and extracted with EtOAc×3. The organic layerswere dried over MgSO₄, filtered, and concentrated. The residue waspurified on SiO₂ by MPLC using a 1:9 to 1:3 EtOAc/hexane gradient.Obtained 424 mg (87% yield) of dimethyl2-((1-(4-fluorophenyl)-1H-indazol-5-yl)methylene)malonate. MS found:(M+H)⁺=355.

(b) Dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)methylene)malonate(424 mg, 1.2 mmol) was dissolved in 10 mL dry THF and 1.0Mphenylmagnesium bromide in THF (5 mL, 5.0 mmol) was added. The reactionmixture was stirred for 12 h. The reaction was quenched with MeOH thenpoured into brine and extracted with EtOAc×3. The organic layers weredried over MgSO₄, filtered, and concentrated. The residue was purifiedon SiO₂ by MPLC and eluting with 1:3 EtOAc/hexane. Obtained 435 mg (84%yield) of dimethyl2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)malonate. MSfound: (M+H)⁺=333.

(c) Dimethyl2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)malonate (250 mg,0.58 mmol) was dissolved in THF (5 mL) and 60% oil dispersion NaH wasadded (24 mg, 0.6 mmol). After 1 h, added DMSO (2 mL) followed by MeI(5.8 mmol). After 72 h, the reaction was quenched with MeOH then pouredinto brine and extracted with EtOAc×3. The organic layers were driedover MgSO₄, filtered, and concentrated. The residue was purified on SiO₂by MPLC using a 1:9 to 1:3 EtOAc/hexane gradient. Obtained 215 mg (83%yield) of dimethyl2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-2-methylmalonate.MS found: (M+H)⁺=447.

(d) Dissolved LiAl(OtBu)3H (509 mg, 2.0 mmol) in 2 mL THF and then addeda solution of dimethyl2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-2-methylmalonate(215 mg, 0.48 mmol) in 2 mL of THF. After 12 h, the reaction wasincomplete so more LiAl(OtBu)3H (509 mg, 2.0 mmol) was added . After 12h, quenched with MeOH, poured into brine and extracted with EtOAc×3. Theorganic layers were dried over MgSO₄, filtered, and concentrated. Theresidue was purified on SiO₂ by MPLC using a 1:3 to 1:1 EtOAc/hexanegradient. Obtained 121 mg (60% yield) of methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(hydroxymethyl)-2-methyl-3-phenylpropanoate.MS found: (M+H)⁺=419.

(e) Methyl3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(hydroxymethyl)-2-methyl-3-phenylpropanoate(121 mg, 0.29 mmol) was dissolved in MeOH (10 mL) and treated with 1 MNaOH (10 mL). After stirring overnight, the MeOH was removed in vacuo,the residue acidified with conc HCl to pH 4-5 and extracted withEtOAc×3. The organic layer was dried with MgSO₄, filtered, concentratedin vacuo to give 115 mg (98%) of3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(hydroxymethyl)-2-methyl-3-phenylpropanoicacid. MS found: (M+H)⁺=405.

(f)3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2-(hydroxymethyl)-2-methyl-3-phenylpropanoicacid (404 mg, 0.28 mmol) was dissolved in 5 mL of dry DCM and pyridine(0.3 mmol) and acetic anhydride (0.3 mmol) were added and then stirred 2h.

The reaction was concentrate in vacuo. The residue was purified on SiO₂by MPLC using a 1:3 to 1:9 gradient of EtOAc/hexane to give 75 mg of2-(acetoxymethyl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoicacid.

(g) Example 154 was prepared from2-(acetoxymethyl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoicacid (75 mg, 0.168 mmol) and 1,3,4-thiadiazol-2-amine using GeneralCoupling Method B to give 35 mg (39% yield). MS found: (M+H)⁺=530.

Example 1553-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2-(hydroxymethyl)-2-methyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(h) Example 155 was prepared from3-(1,3,4-thiadiazol-2-ylamino)-2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-2-methyl-3-oxopropylacetate (24 mg, 0.168 mmol) by treating with 1N HCl in CH3CN and heatingfor 1 hr at reflux. The product was purified by HPLC to give 6 mg ofdesired product. MS found: (M+H)⁺=48.

Example 1562-(5-((S)-3-(1,3,4-Thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluorobenzamide

(a) A suspension of (5 mg, 0.01 mmol) and Na₂O₂ (11 mg, 0.15 mmol) inwater (1 mL) was stirred under nitrogen at 70° C. for 30 min.Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run,solvent A: 10% MeOH: 90% H₂O: 0.1% TFA, solvent B: 90% MeOH, 10% H₂O,0.1% TFA) gave2-(5-((S)-3-(1,3,4-thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluorobenzamide;Example 156 (3 mg, 0.006 mmol, 60% yield) as a white solid. MS found:(M+H)⁺=515. ¹H-NMR (500 MHz, METHANOL-d₃) δ ppm 8.96 (s, 1H) 8.17 (s,1H) 7.88 (s, 1H) 7.58 (dd, J=8.80, 4.67 Hz, 1H) 7.49 (dd, J=8.39, 2.89Hz, 1H) 7.38-7.44 (m, 4H) 7.31 (d, J=9.07 Hz, 1H) 7.25 (t, J=7.56 Hz,2H) 7.15-7.19 (m, 1H) 4.81 (s, 1H) 1.45 (s, 3H) 1.44 (s, 3H).

Example 1572-(5-((S)-3-(1,3,4-Thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluorobenzoicacid

(b) A suspension of(3S)-3-(1-(2-cyano-4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide(35 mg, 0.072 mmol) and Na₂O₂ (77 mg, 1.1 mmol) in water (7 mL) wasstirred under nitrogen at 70° C. for 30 min and at 90° C. for 1 day. Themixture was acidified with 10% aqueous citric acid solution to pH=2 andextracted with ethyl acetate (3×5 mL). The combined ethyl acetateextracts were concentrated in vacuo. Purification using reverse phaseHPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H₂O: 0.1%TFA, solvent B: 90% MeOH, 10% H₂O, 0.1% TFA) gave2-(5-((S)-3-(1,3,4-thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluorobenzoicacid; Example 157 (24 mg, 0.047 mmol, 64% yield) as a yellow solid. MSfound: (M+H)⁺=516. ¹H-NMR (500 MHz, METHANOL-d₃) δ ppm 8.95 (s, 1H) 8.16(s, 1H) 7.89 (s, 1H) 7.72 (dd, J=8.80, 3.02 Hz, 1H) 7.60 (dd, J=8.66,4.81 Hz, 1H) 7.49 (td, J=8.25, 3.02 Hz, 1H) 7.39-7.43 (m, 3H) 7.15-7.27(m, 4H) 4.82 (s, 1H) 1.46 (s, 3H) 1.44 (s, 3H).

Example 1582-(5-((S)-3-(1,3,4-Thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluoro-N,N-dimethylbenzamide

Example 159(3S)-3-(1-(2-Amino-4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

Example 160(3S)-3-(1-(2-(3,3-Dimethylureido)-4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(c)(d) A mixture of2-(5-((S)-3-(1,3,4-thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluorobenzoicacid (9.4 mg, 0.018 mmol), diisopropylethylamine (0.01 mL), andanhydrous toluene (0.2 mL) was degassed and backfilled with nitrogen.After DPPA (0.01 mL, 0.046 mmol) was added, the mixture was heated to100° C. over 20 min and then cooled to RT. Diisopropylethylamine (0.02mL) and dimethylamine hydrochloride (100 mg, 1.2 mmol) were addedsequentially. The reaction mixture was then stirred at RT for 1 hr andat 80° C. for 3 hr before concentrated in vacuo. Purification usingreverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH:90% H₂O: 0.1% TFA, solvent B: 90% MeOH, 10% H₂O, 0.1% TFA) gave:

1)2-(5-((S)-3-(1,3,4-Thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluoro-N,N-dimethylbenzamide;Example 158 (2 mg, 0.0037 mmol, 20% yield) as a glassy solid. MS found:(M+H)⁺=543. ¹H-NMR (500 MHz, methanol-d₃) δ ppm 8.95 (s, 1H) 8.14 (s,1H) 7.89 (s, 1H) 7.67 (dd, J=8.80, 4.95 Hz, 1H) 7.39-7.44 (m, 5H) 7.32(dd, J=8.39, 2.89 Hz, 1H) 7.26 (t, J=7.84 Hz, 2H) 7.16-7.20 (m, 1H) 4.82(s, 1H) 2.74 (s, 3H) 2.59 (s, 3H) 1.46 (s, 3H) 1.44 (s, 3H);

2)(3S)-3-(1-(2-Amino-4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide;Example 159 (1.6 mg, 0.003 mmol, 15% yield) as a glassy solid. MS found:(M+H)⁺=487. ¹H-NMR (500 MHz, METHANOL-d₃) δ ppm 8.95 (s, 1H) 8.20 (s,1H) 7.90 (s, 1H) 7.40-7.44 (m, 3H) 7.25 (t, J=7.56 Hz, 2H) 7.19 (dd,J=8.11, 3.44 Hz, 2H) 7.14 (dd, J=8.66, 5.91 Hz, 1H) 6.65 (dd, J=11.00,2.75 Hz, 1H) 6.47 (td, J=8.39, 2.75 Hz, 1H) 4.82 (s, 1H) 1.46 (s, 3H)1.45 (s, 3H); and

3)(3S)-3-(1-(2-(3,3-Dimethylureido)-4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide;Example 160 (3 mg, 0.005 mmol, 30% yield) as a white solid. MS found:(M+H)⁺=558. ¹H-NMR (500 MHz, methanol-d₃) δ ppm 8.96 (s, 1H) 8.30 (s,1H) 7.94 (s, 1H) 7.89 (ddd, J=11.13, 4.81, 3.02 Hz, 1H) 7.40-7.51 (m,4H) 7.35 (d, J=8.80 Hz, 1H) 7.26 (t, J=7.70 Hz, 2H) 7.16-7.21 (m, 1H)6.93-6.99 (m, 1H) 4.84 (s, 1H) 2.77 (s, 6H) 1.47 (s, 3H) 1.45 (s, 3H).

Example 161(3S)-3-(1-(4-Fluoro-2-ureidophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide

(e)(f) A mixture of2-(5-((S)-3-(1,3,4-thiadiazol-2-ylamino)-2,2-dimethyl-3-oxo-1-phenylpropyl)-1H-indazol-1-yl)-5-fluorobenzoicacid (12 mg, 0.023 mmol), diisopropylethylamine (0.01 mL), anhydroustoluene (0.2 mL), and DPPA (0.01 mL, 0.046 mmol) was heated to 100° C.over 25 min under nitrogen and stirred at 100° C. for 10 min beforecooled to RT. An ammonia solution (0.5 M in dioxane, 0.4 mL, 0.2 mmol)was added. The reaction mixture was stirred at RT overnight beforeconcentrated in vacuo. Purification using reverse phase HPLC (YMC S520×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H₂O: 0.1% TFA, solventB: 90% MeOH, 10% H₂O, 0.1% TFA) gave(3S)-3-(1-(4-fluoro-2-ureidophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenyl-N-(1,3,4-thiadiazol-2-yl)propanamide; Example 161 (2.3 mg, 0.0043 mmol, 19%yield). MS found: (M+H)⁺=530. ¹H-NMR (400 MHz, MeOD) δ ppm 8.96 (s, 1H)8.26 (s, 1H) 8.07 (dd, J=11.58, 2.77 Hz, 1H) 7.93 (s, 1H) 7.39-7.47 (m,3H) 7.15-7.28 (m, 5H) 6.88 (td, J=8.25, 2.90 Hz, 1H) 4.84 (s, 1H) 1.47(s, 3H) 1.44 (s, 3H).

Example 162

(a) A mixture of ethyl 3-oxo-3-phenylpropanoate (17.2 mL, 100 mmol),triethyl orthoformate (24.5 mL, 150 mmol), and acetic anhydride (38 mL,400 mmol) was stirred at 135° C. for 5 hr. Distillation under reducedpressure gave ethyl 2-benzoyl-3-ethoxyacrylate (14.7 g, 59 mmol, 59%yield) as a yellow liquid.

(b) A mixture of ethyl 2-benzoyl-3-ethoxyacrylate (0.99 g, 4.0 mmol) and1-phenyl-1H-pyrazol-5-amine (0.64 g, 4.0 mmol) was stirred at 120° C.for 1.5 hr under argon and then cooled. After diphenyl ether (5 g) wasadded, the mixture was stirred at 240° C. for 2 hr under argon. Flashchromatography and crystallization in heptane and ethyl acetate mixturegave(4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone(0.53 g, 1.7 mmol, 42% yield) as a yellow solid.

(c) A mixture of(4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone(0.38 g, 1.2 mmol) and phosphorus oxychloride (1.3 mL) was stirred at110° C. for 1.5 hr. The mixture was cooled, poured onto ice, basifiedwith sodium hydroxide aqueous solution to pH=8, and extracted with ethylacetate. Combined extracts were dried (Na₂SO₄) and concentrated. Flashchromatography gave(4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone(0.26 g, 0.79 mmol, 66% yield) as a yellow solid.

(d) To a stirred solution of(4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone(0.16 g, 0.48 mmol) in THF (1.5 mL) and ethanol (95%, 1.5 mL) was addedsodium borohydride (30 mg, 0.79 mmol). The mixture was stirred at rt for30 min before saturated ammonium chloride aqueous solution was addedwith caution. The mixture was concentrated and partitioned between waterand ethyl acetate. The aqueous layer was separated and extracted withethyl acetate. Combined organic solutions were dried (Na₂SO₄), filteredthrough a pad of silica gel, and concentrated to give(4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanol (0.16g, 0.48 mmol, 100% yield) as a yellow solid.

(e) (4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanolwas converted to methyl3-(4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,2-dimethyl-3-phenylpropanoateusing the procedure of Example 1(g).

(f) A mixture of methyl3-(4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,2-dimethyl-3-phenylpropanoate(27 mg, 0.064 mmol), palladium (10% on carbon, 10 mg),diisopropylethylamine (0.017 mL, 0.096 mmol), and ethanol (3 mL) wasstirred under hydrogen balloon for 80 min. The mixture was then filteredthrough a pad of silica gel and concentrated. The residue was mixed withlithium hydroxide monohydrate (30 mg, 0.7 mmol), water (1 mL), anddioxane (1 mL), and stirred at 110° C. overnight. After cooled, themixture was partitioned between water and diethyl ether. The ether layerwas extracted with water. Combined aqueous solutions were acidified with10% citric acid aqueous solution and extracted with ethyl acetate.Combined extracts were washed with brine, dried (Na₂SO₄) andconcentrated to give2,2-dimethyl-3-phenyl-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)propanoicacid (16 mg, 0.043 mmol, 69% yield).

(g) To a stirred solution of2,2-dimethyl-3-phenyl-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)propanoicacid (8 mg, 0.022 mmol), 2-aminothiazole (9 mg, 0.09 mmol), anddiisopropylethylamine (0.015 mL, 0.09 mmol) in anhydrous DMF (0.3 mL)was added HATU (33 mg, 0.09 mmol) under argon. After stirred at rtovernight and 80° C. for 30 min, the mixture was concentrated. HPLCpurification gave2,2-dimethyl-3-phenyl-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(thiazol-2-yl)propanamide(Example 162, 5 mg, 0.009 mmol, 41% yield) as a trifluoroacetic acidsalt. MS found: (M−H)⁻=452.11. ¹H-NMR (400 MHz, Acetone) δ ppm 8.56 (1H,d, J=2.54 Hz) 8.39 (1H, d, J=2.03 Hz) 8.24 (2H, d, J=7.63 Hz) 8.18 (1H,s), 7.37-7.47 (4H, m) 7.27 (1H, d, J=3.56 Hz) 7.16-7.23 (3H, m) 7.11(1H, t, J=7.38 Hz) 6.95 (1H, d, J=3.56 Hz) 4.98 (1H, s) 1.42 (6H, d,J=7.63 Hz).

BIOLOGICAL ACTIVITY

Below is a Table containing activity for Examples 1 to 162. (R) and (S)refer to absolute stereochemistry. “Enant A” and “enant B” refer toenantiomerically pure compounds of unknown configuration that wereresolved by chiral HPLC and are arbitrarily assigned. “Diast A” and“diast B” refer to diastereomerically pure compounds of unknown relativestereochemistry. “Isomer A” “isomer B” “isomer C” and “isomer D” referto two enantiomeric pairs of two diastereomers all resolved by chiralHPLC and are arbitraily assigned.

Biological Activity Table GR (Ki, nM) GR (Ki, nM) AP-1 (EC50, nM) (GRBinding (GR Binding (Cellular Transrepression Example No. Assay (I))Assay (II)) Assay) (S)-1 6.0 0.81 (R)-1 7.9 400 (S)-2 5.1 2.4 (R)-2 6.792  3 6.9 199  4 7 12  5 7.0 1328  6 77 >10000  7 2.9 904  8 3.0 1796  93.7 3058  10 227 3521  11 11 73  12 14 29  13 11 17  14 17 >10000  15318 >10000  16 163 >10000  17 11 49  18 21 141  19 47 >10000  2010 >10000  21 12 155  22 29 840  23 60 >10000  24 28 >10000  2519 >10000  26 16 404  27 23 1307  28 20 647  29 7.8 126 (S)-30 0.54 24(R)-30 13 701  31 98 >10000  32 84 4322 33-enant A 18 >10000 33-enant B13 11  34 7.5 29  35 21 82  36 12 389  37 301 3350 38-enant A 15 1238-enant B 14 >10000  39 9.8 87  40 1.6 2.1  41 2.3 2.6  42 1.9 3.9  432.9 2.4  44 2.4 14  45 2.6 52  46 1.7 18  47 1.7 523  48 2.4 81  49 1.14.2  50 0.92 9.7  51 1.8 3.9  52 1.3 8.1  53 1.9 13 54-enant A 1.2 5.854-enant B 0.90 3.2  55 1.3 2500  56 1.3 4  57 20 205  58 10 177  59543 >10000  60 29 >10000  61 14 158  62 9 6147  63 10 301  64 65 >10000 65 47 550 66-enant A 5.7 62 66-enant B 16 1698  67 25 532 68-enant A6.1 192 68-enant B 32 7711  69 84 >10000  70 19 1015  71 28 >10000  7214 1932  73 46 >10000  74 152 >10000  75 17 1021  76 9.3 267  77 23 951 78 12 29  79 10 2485  80 8.1 127  81 11 1292  82 20 491  83 8.8 230  847.2 306  85 7.8 40 86-enant A 3.7 95 86-enant B 4.0 >10000  87 5.0 20 88 26 >10000  89 27 >10000  90 85 >10000  91 29 956  92 110 >10000  9318 32  94 36 1196  95 496 >10000  96 3.1 23  97 5.5 >2500  98 15 34 99 >10000 100 102 290 101 1.0 36 102 2.8 12 103 248 >10000 1041.6 >10000 105 5.6 1.9 106 1.0 160 107 7.8 193 108 6.6 1195 10959 >10000 110 13 220 111-enant A 73 1087 111-enant B 25 777 112 13 2413113 5.1 107 114 11 >10000 115 26 3645 116 43 3256 117 57 3614 118 952929 119 146 2132 120 5.8 74 121 8.3 1729 122 2.3 >10000 123 1.1 705124-isomerA 7.5 >10000 124-isomerB 2.3 >10000 124-isomerC 2.1 1251124-isomerD 0.64 40 125 9.9 >10000 126 6.8 >10000 127 3.8 >10000 1280.68 673 129 0.87 106 130 6.1 >10000 131 3.0 >10000 132 7.8 >10000 133153 >10000 134 6.0 >10000 135 0.6 40 136-enant A 23 >10000 136-enant B6.0 13 137 11 833 138 1.9 223 139 4.7 2500 140 1.6 4 141-isomerA 44 453141-isomerB 0.59 17 141-isomerC 0.48 0.23 141-isomerD 2.4 20 142 1.10.55 143 1.7 2 144 2.0 2 145-isomerA 18 5000 145-isomerB 1.1 5145-isomerC 555 5000 145-isomerD 2.4 45 146 1.5 2 147 2.3 2 148 6.4 6149 4.7 130 150 4.0 13 151-diast A 1.6 9 151-diast B 283 1736 152-diastA 9.8 2500 152-diast B 1154 5000 153 4.3 27 154 2.6 15 155 4.3 1771 15622 135 157 634 — 158 825 2500 159 0.35 73 160 25 234 161 32 5000 162 3.63559

1. A compound according to formula I,

its enantiomers, diastereomers, tautomers, a prodrug ester thereof, or apharmaceutically-acceptable salt, or hydrate, thereof, wherein: the sidechain group

is attached to the bicyclic ring

at the 5- or 6-position;

is heterocyclo or heteroaryl; E is selected from —N—, —NR₁—, —O—,C(═O)—, —S—, —SO₂—, and —CR₂—; F is selected from —N—, —NR_(1a)—, —O—,—C(═O)—, —S—, SO₂—, and —CR_(2a)—; G is selected from N, —NR_(1b)—, —O—,—C(═O)—, —S—, SO₂—, and —CR_(2b)—, provided that the E-F-G containingheterocyclic ring formed does not contain a S—S or S—O bond, and atleast one of E, F and G is a heteroatom; J is C or N; J_(a) is C or N,provided that only one of J and J_(a) can be N, and each of J and J_(a)can be C; and that when E is CR₂, F is N and G is NR_(1b), then J_(a) isC; M is selected from hydrogen, alkyl, alkenyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl and heterocyclo other than piperidinyl;M_(a) is a linker between C and M and is selected from a bond; C₁-C₅alkylene; C₁-C₅ alkylene which includes at any position in the chain a)a nitrogen which is substituted with alkyl, b) an oxygen, c) a sulfur,or d) an SO₂ group; —C(R_(m) ₁ )(R_(m) ₂ )C(═O)N(R_(m) ₃ )—; —C(R_(m) ₁)(R_(m) ₂ )S(═O)₂N(R_(m) ₃ )—; Oalkyl; —N(R_(m) ₃ )C(═O)C(R_(m) ₁)(R_(m) ₂ )—; —S(═O)₂N(R_(m) ₁ )C(R_(m) ₂ )(R_(m) ₃ )—; and —N(R_(m) ₁)C(═O)N(R_(m) ₂ )—; where R_(m) ₁ , R_(m) ₂ and R_(m) ₃ are the same ordifferent and at each occurrence independently selected from H and C₁-C₄alkyl, or R_(m) ₁ and R_(m) ₂ combine to form a C₃₋₆ carbocyclic orheterocyclo ring; Q is selected from (i) hydrogen, halogen, nitro,cyano, hydroxy, and C₁-C₄ alkyl; or (ii) Q and R₆ are combined with thecarbons to which they are attached to form a 3- to 6-memberedcycloalkyl; or (iii) Q and -M_(a)-M are combined with the carbons towhich they are attached to form a 3- to 7-membered ring containing 0, 1or 2 heteroatoms which are the same or different and are independentlyselected from the group consisting of O, S, SO₂, and

which ring may be optionally substituted with 0-2 R₃ groups or carbonyl;Z is selected from alkyl, cycloalkyl, heterocyclo, aryl, alkylsulfonyl,and heteroaryl other than substituted or unsubstituted 4-pyridyl; Z_(a)is a linker between N and Z and is selected from a bond; C₁-C₅ alkylene;C₁-C₅ alkylene which includes at any position in the chain a nitrogenwhich is substituted with alkyl or an SO₂ group; —C(R_(z) ₁ )(R_(z) ₂)C(═O)N(R_(z) ₃ )—; —C(═O)N(R_(z) ₁ )C(R_(z) ₂ )(R_(z) ₃ )—; —C(R_(z) ₁)(R_(z) ₂ )S(═O)₂N(R_(z) ₃ )—; or —S(═O)₂N(R_(z) ₁ )C(R_(z) ₂ )(R_(z) ₃)—; where R_(z) ₁ , R_(z) ₂ and R_(z) ₃ at each occurrence areindependently selected from H and C₁-C₄ alkyl; R₁, R_(1a) and R_(1b) arethe same or different and at each occurrence are independently selectedfrom hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, and heterocyclo; R₂, R_(2a) and R_(2b) are the same ordifferent and at each occurrence are independently selected fromhydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR₁₀,—NR₁₀R₁₁, —C(═O)R₁₀, —CO₂R₁₀, —C(═O)NR₁₀R₁₁, —O—C(═O)R₁₀, —NR₁₀C(═O)R₁₁,—NR₁₀C(═O)OR₁₁, —NR₁₀C(S)OR₁₁, —S(═O)_(p)R₁₂, —NR₁₀SO₂R₁₂, —SO₂NR₁₀R₁₁,cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, andheteroaryl; R₃ at each occurrence is independently selected fromhydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR₁₃,—NR₁₃R₁₄, —C(═O)R₁₃, —CO₂R₁₃, —C(═O)NR₁₃R₁₄, —O—C(═O)R₁₃, —NR₁₃C(═O)R₁₄,—NR₁₃C(═O)OR₁₄, —NR₁₃C(S)OR₁₄, —S(═O)_(p)R₁₅, —NR₁₃SO₂R₁₅, —SO₂NR₁₃R₁₄,cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, andheteroaryl; R₄ is selected from hydrogen, alkyl, halogen, and C₁-C₄alkoxy; R₆ is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl,nitro, cyano, —OR₁₆, —NR₁₆R₁₇, —C(═O)R₁₇, —CO₂R₁₇, —C(═O)NR₁₆R₁₇,—O—C(═O)R₁₆, —NR₁₆C(═O)R₁₇, —NR₁₆C(═O)OR₁₇, —NR₁₆C(═S)OR₁₇,—S(═O)_(p)R₁₈, —NR₁₆SO₂R₁₈, —SO₂NR₁₆R₁₇, cycloalkyl, cycloalkenyl,heterocyclo, aryl, and heteroaryl; R₇ is selected from hydrogen,halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR₁₉, —NR₁₉R₂₀,—C(═O)R₁₉, —CO₂R₁₉, —C(═O)NR₁₉R₂₀, —O—C(═O)R₁₉, —NR₁₉C(═O)R₂₀,—NR₁₉C(═O)OR₂₀, —NR₁₉C(═S)OR₂₀, —S(═O)_(p)R₂₁, —NR₁₈SO₂R₂₁, —SO₂NR₁₉R₂₀,cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, andheteroaryl; or R₆ and R₇ are taken together with the carbon to whichthey are attached to form a cycloalkyl, cycloalkenyl, or heterocyclogroup; R₅, R₁₀, R₁₁, R₁₃, R₁₄, R₁₆, R₁₇, R₁₉ and R₂₀ are the same ordifferent and at each occurrence are independently selected from (i)hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, and heterocyclo; or (ii) with respect to R₃, R₁₃ is takentogether with R₁₀; and/or with respect to R₆, R₁₆ is taken together withR₁₇; and/or with respect to R₇, R₁₉ is taken together with R₂₀ to form a4- to 6-membered heteroaryl or heterocyclo ring; R₁₂, R₁₅, R₁₈, and R₂₁are the same or different and are independently selected from alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, orheterocyclo; and p is 0, 1 or 2, provided that 1) at least one of Q,M_(a)-M, R₆ and R₇ must be other than hydrogen; or 2) when Q and R₆ (andthe carbons to which they are attached) combine to form a 3- to7-membered carbocyclic ring, then —Z_(a)—Z cannot be C₁-C₅ alkyl; or 3)when Q and M_(a)-M combine to form a 3- to 7-membered carbocyclic ring,then —Z_(a)—Z cannot be C₁-C₅ alkyl; or 4) when Z_(a) is a bond, then Zis other than


2. The compound as defined in claim 1 wherein

is selected from

wherein each of the above ring systems may optionally include an R₄group.
 3. The compound as defined in claim 1 wherein E is CR₂ or NR₁; Fis N, NR_(1a) or CR_(2a); and G is NR_(1b) or CR_(2b); and one of J_(a)or J is optionally N.
 4. The compound as defined in claim 1 a) where Eis NR₁, F is CR_(2a) and G is CR_(2b), or G is NR_(1b), F is CR_(2a) andE is CR₂ so that the resulting bicyclic ring is an indole, then R_(1a),R_(2a) and/or R_(2b) cannot be —NH₂; or b) where E is NR₁, F is N, and Gis CR_(2b) or G is NR_(1b), F is N and E is CR₂, so that the resultingbicyclic ring is an indazole, then R₁, R_(1b), R₂ and R_(2a) cannot beNH₂; or c) when the bicyclic ring is an indazole and Q and M-M_(a) (andthe carbon to which they are attached) combine to form a 5- or6-membered ring, then —Z_(a)—Z cannot be C₁-C₅ alkyl; or d) when thebicyclic ring is an indazole, Q and M-M_(a) (and the carbon to whichthey are attached) cannot combine to form a cyclohexane ring, or acyclohexene ring or a cyclohexadiene ring; or e) when the bicyclic ringis an indazole and R₆ or R₇ is independently H or C₁-C₇ alkyl, thenZ_(a) cannot be (CH₂)₀₋₄.
 5. The compound as defined in claim 1 whereinwhen -M_(a)-M is alkyl, aryl, or heteroaryl, then —Z_(a)—Z is other thanC₁-C₇ alkyl or aryl.
 6. The compound as defined in claim 1 where thebicyclic ring is an indazole or indole of the structure

wherein the side chain group is linked to the 5-position and not the6-position.
 7. The compound as defined in claim 3 wherein G is N—R_(1b)and R_(1b) is selected from H, aryl, alkyl, heterocyclo,alkylsulfonylalkyl, heteroaryl, and hydroxyalkyloxyalkyl; Z—Z_(a)— isselected from heteroaryl, cycloalkyl, alkylsulfonyl, haloalkylsulfonyl,and haloalkyl; M-M_(a) is selected from aryl, alkyl, cycloalkyl,heteroaryl, arylalkyl, and hydroxyheteroaryl; Q is hydrogen, or alkyl;or Q and M-M_(a) and the carbons to which they are attached combine toform a heterocyclo ring, or a cycloalkyl; or Q and R₆ and the carbons towhich they are attached combine to form a heterocyclo ring, or acycloalkyl ring.
 8. The compound as defined in claim 3 where R_(1b) ishaloalkylaryl, haloaryl, haloalkylalkyl(halo)aryl, alkoxyaryl,alkoxycarbonylaryl, H, hydroxyalkyl, heterocyclo, alkylheterocyclo,alkylsulfonylalkyl, alkyl, heteroaryl, hydroxyaryl, alkoxyalkyl,arylalkyl, cycloalkyl, alkoxycarbonylaryl, or carboxyaryl; Z is selectedfrom unsubstituted heteroaryl, alkoxycarbonylheteroaryl,alkylheteroaryl, cycloalkyl, aminoheteroaryl, cycloheteroaryl,cycloalkylheteroaryl, hydroxyheteroaryl, alkylthioheteroaryl,dialkylheteroaryl, haloalkylheteroaryl, haloheteroaryl,hydroxycycloalkyl, aminocycloalkyl, alkylcarbonylaminocycloalkyl,unsubstituted alkylsulfonyl, haloalkylsulfonyl, unsubstituted alkyl, andhaloalkyl; or Z is heteroaryl substituted with one, two or three groupswhich are the same or different and are independently selected fromhydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, OR₁ ^(c), NR₁^(a)R₁ ^(b), C(═O)R₁ ^(c), CO₂R₁ ^(c), C(═O)NR₁ ^(a)R₁ ^(b), —O—C(═O)R₁^(c), NR₁ ^(a)C(═O)R₁ ^(b), NR₁ ^(a)C(═O)OR₁ ^(b), NR₁ ^(a)C(═S)OR₁^(b), S(═O)_(p) ₁ R₁ ^(c), NR₁ ^(a)SO₂R₁ ^(b), SO₂NR₁ ^(a)R₁ ^(b),cycloalkyl, cycloalkenyl, heterocyclo, aryl, or heteroaryl; and R₁ ^(a),R₁ ^(b), and R₁ ^(c), are the same or different and are independentlyselected from (i) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possibleR^(a) is taken together with R^(b) to form a heteroaryl or heterocycloring; p₁ is 0, 1 or 2; M is alkyl, aryl, cycloalkyl, heteroayl,arylalkyl, heterocyclo, alkylarylalkyl, alkylaryl, or haloaryl; M_(a) isa bond or alkyl; Q is H or alkyl, or Q and R₆ and the carbons to whichthey are attached combine to form

Q and M-M_(a) and the carbons to which they are attached can be combinedto form


9. A compound as defined in claim 1 wherein: Z is selected from

R^(m) and R^(n) are the same or different and at each occurrence areindependently selected from hydrogen, halogen, cycloalkyl, cyano,haloalkyl, thioalkyl, —CO₂R^(c), —NR^(a)R^(b), —C(═O)R^(c),—C(O)N(R^(a))(R^(b)), OR^(c), unsubstituted alkyl, aryl, heteroaryl andheterocyclo; or R^(m) and R^(n) combine to form a 5-, 6- or 7-memberedcarbocyclic, aryl, heteroaryl or cycloheteroalkyl ring which contains 0,1, 2 or 3 hetero atoms which can be N, O, or S; R^(a) and R^(b) are thesame or different and at each occurrence are independently selected fromhydrogen, alkyl, C(═O)alkyl, CO₂(alkyl), SO₂alkyl, alkenyl, alkynyl,amino, substituted amino (NR^(a)R^(b)), aryl, heteroaryl, cycloalkenyl,heterocyclo, and cycloalkyl, provided R^(a) and R^(b) are not bothalkoxy, amino, or substituted amino, or where possible R^(a) is takentogether with R^(b) to form a heteroaryl or heterocyclo ring; R^(c) isselected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino,substituted amino, heteroaryl, heterocyclo, cycloalkyl, and aryl; andR^(o) is selected from alkyl, aryl, heteroaryl and heterocyclo; or R^(m)and R^(n) combine to form a 5-, 6- or 7-membered carbocyclic, aryl,heteroaryl or heterocyclo ring which contains 0, 1, 2 or 3 hetero atomswhich can be N, O or S.
 10. The compound as defined in claim 1 wherein Eis CR₂ or NR₁; F is N, NR_(1a) or CR_(2a); G is NR_(1b) or CR_(2b); R₁is CH, H or —C═O; R_(1a) is H,

R_(2a) is

R_(1b) is

—Z_(a)—Z is

-M_(a)-M is CH₃

Q is H or CH₃; or Q and R₆ together with the carbons to which they areattached can be combined to form

Q and M-M_(a) together with the carbons to which they are attached canbe combined to form

R₄ is H or CH₃; R₆ is CH₃, C₂H₅, C₃H₇, i-C₃H₇, or H or is combined withQ as described above; R₇ is CH₃, C₂H₅, C₃H₇, i-C₃H₇, C₆H₅, —CH₂C₆H₅,

—CH₂OC(═O)CH₃, —CH₂OH, or H.
 11. The compound as defined in claim 1having the structure

or a pharmaceutically acceptable salt thereof.
 12. The compound havingthe structure

or a pharmaceutically acceptable salt thereof.
 13. A method of treatinga disease or disorder selected from a metabolic disease and aninflammatory or immune disease comprising administering to a patient inneed of treatment, a therapeutically effective amount of a compound asdefined in claim
 1. 14. A pharmaceutical composition comprising acompound as defined in claim 1 and a pharmaceutically acceptable carriertherefor.
 15. A pharmaceutical combination comprising a compound asdefined in claim 1 and an immunosuppressant, an anticancer agent, ananti-viral agent, an anti-inflammatory agent, an anti-fungal agent, ananti-biotic, an anti-vascular hyperproliferation agent, ananti-depressant agent, a lipid-lowering agent, a lipid modulating agent,an antidiabetic agent, an anti-obesity agent, an antihypertensive agent,a platelet aggregation inhibitor, and/or an antiosteoporosis agent,wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, asulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γdual agonist, an SGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, aninsulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and/or ameglitinide, wherein the anti-obesity agent is a beta 3 adrenergicagonist, a lipase inhibitor, a serotonin (and dopamine) reuptakeinhibitor, a thyroid receptor agonist, an aP2 inhibitor and/or ananorectic agent, wherein the lipid-lowering agent is an MTP inhibitor,an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, afibric acid derivative, an upregulator of LDL receptor activity, alipoxygenase inhibitor, or an ACAT inhibitor, wherein theantihypertensive agent is an ACE inhibitor, angiotensin II receptorantagonist, NEP/ACE inhibitor, calcium channel blocker and/orβ-adrenergic blocker.